http://www.geneimprint.com/ Recent articles of special importance in the field of genomic imprinting. en-us Fri, 19 Apr 2013 14:24:19 PDT Fri, 19 Apr 2013 14:24:19 PDT jirtle@radonc.duke.edu james001@jirtle.com Susiarjo M, Sasson I, Mesaros C, Bartolomei MS
PLoS Genet (Apr 2013)

Exposure to endocrine disruptors is associated with developmental defects. One compound of concern, to which humans are widely exposed, is bisphenol A (BPA). In model organisms, BPA exposure is linked to metabolic disorders, infertility, cancer, and behavior anomalies. Recently, BPA exposure has been linked to DNA methylation changes, indicating that epigenetic mechanisms may be relevant. We investigated effects of exposure on genomic imprinting in the mouse as imprinted genes are regulated by differential DNA methylation and aberrant imprinting disrupts fetal, placental, and postnatal development. Through allele-specific and quantitative real-time PCR analysis, we demonstrated that maternal BPA exposure during late stages of oocyte development and early stages of embryonic development significantly disrupted imprinted gene expression in embryonic day (E) 9.5 and 12.5 embryos and placentas. The affected genes included Snrpn, Ube3a, Igf2, Kcnq1ot1, Cdkn1c, and Ascl2; mutations and aberrant regulation of these genes are associated with imprinting disorders in humans. Furthermore, the majority of affected genes were expressed abnormally in the placenta. DNA methylation studies showed that BPA exposure significantly altered the methylation levels of differentially methylated regions (DMRs) including the Snrpn imprinting control region (ICR) and Igf2 DMR1. Moreover, exposure significantly reduced genome-wide methylation levels in the placenta, but not the embryo. Histological and immunohistochemical examinations revealed that these epigenetic defects were associated with abnormal placental development. In contrast to this early exposure paradigm, exposure outside of the epigenetic reprogramming window did not cause significant imprinting perturbations. Our data suggest that early exposure to common environmental compounds has the potential to disrupt fetal and postnatal health through epigenetic changes in the embryo and abnormal development of the placenta.]]> Wed, 17 Apr 2013 00:00:00 PDT Court F, Martin-Trujillo A, Romanelli V, Garin I, Iglesias-Platas I, Salafsky I, Guitart M, Perez de Nanclares G, Lapunzina P, Monk D
Hum Mutat (Apr 2013)

Genomic imprinting is the parent-of-origin-specific allelic transcriptional silencing observed in mammals, which is governed by DNA methylation established in the gametes and maintained throughout the development. The frequency and extent of epimutations associated with the nine reported imprinting syndromes varies because it is evident that aberrant preimplantation maintenance of imprinted differentially methylated regions (DMRs) may affect multiple loci. Using a custom Illumina GoldenGate array targeting 27 imprinted DMRs, we profiled allelic methylation in 65 imprinting defect patients. We identify multilocus hypomethylation in numerous Beckwith-Wiedemann syndrome, transient neonatal diabetes mellitus (TNDM), and pseudohypoparathyroidism 1B patients, and an individual with Silver-Russell syndrome. Our data reveal a broad range of epimutations exist in certain imprinting syndromes, with the exception of Prader-Willi syndrome and Angelman syndrome patients that are associated with solitary SNRPN-DMR defects. A mutation analysis identified a 1 bp deletion in the ZFP57 gene in a TNDM patient with methylation defects at multiple maternal DMRs. In addition, we observe missense variants in ZFP57, NLRP2, and NLRP7 that are not consistent with maternal effect and aberrant establishment or methylation maintenance, and are likely benign. This work illustrates that further extensive molecular characterization of these rare patients is required to fully understand the mechanism underlying the etiology of imprint establishment and maintenance.]]> Fri, 22 Mar 2013 00:00:00 PDT Merkenschlager M, Odom DT
Cell (Mar 2013)

Current epigenomics approaches have facilitated the genome-wide identification of regulatory elements based on chromatin features and transcriptional regulator binding and have begun to map long-range interactions between regulatory elements and their targets. Here, we focus on the emerging roles of CTCF and the cohesin in coordinating long-range interactions between regulatory elements. We discuss how species-specific transposable elements may influence such interactions by remodeling the CTCF binding repertoire and suggest that cohesin's association with enhancers, promoters, and sites defined by CTCF binding has the potential to form developmentally regulated networks of long-range interactions that reflect and promote cell-type-specific transcriptional programs.]]> Mon, 18 Mar 2013 00:00:00 PDT Soubry A, Schildkraut JM, Murtha A, Wang F, Huang Z, Bernal A, Kurtzberg J, Jirtle RL, Murphy SK, Hoyo C
BMC Med (Jan 2013)

Data from epidemiological and animal model studies suggest that nutrition during pregnancy may affect the health status of subsequent generations. These transgenerational effects are now being explained by disruptions at the level of the epigenetic machinery. Besides in vitro environmental exposures, the possible impact on the reprogramming of methylation profiles at imprinted genes at a much earlier time point, such as during spermatogenesis or oogenesis, has not previously been considered. In this study, our aim was to determine associations between preconceptional obesity and DNA methylation profiles in the offspring, particularly at the differentially methylated regions (DMRs) of the imprinted Insulin-like Growth Factor 2 (IGF2) gene.]]> Fri, 01 Mar 2013 00:00:00 PST Rice WR, Friberg U, Gavrilets S
Q Rev Biol (Dec 2012)

Male and female homosexuality have substantial prevalence in humans. Pedigree and twin studies indicate that homosexuality has substantial heritability in both sexes, yet concordance between identical twins is low and molecular studies have failed to find associated DNA makers. This paradoxical pattern calls for an explanation. We use published data on fetal androgen signaling and gene regulation via nongenetic changes in DNA packaging (epigenetics) to develop a new model for homosexuality. It is well established that fetal androgen signaling strongly influences sexual development. We show that an unappreciated feature of this process is reduced androgen sensitivity in XX fetuses and enhanced sensitivity in XY fetuses, and that this difference is most feasibly mused by numerous sex-specific epigenetic modifications ("epi-marks") originating in embryonic stem cells. These epi-marks buffer XX fetuses from masculinization due to excess fetal androgen exposure and similarly buffer XY fetuses from androgen underexposure. Extant data indicates that individual epi-marks influence some but not other sexually dimorphic traits, vary in strength across individuals, and are produced during ontogeny and erased between generations. Those that escape erasure will steer development of the sexual phenotypes they influence in a gonad-discordant direction in opposite sex offspring, mosaically feminizing XY offspring and masculinizing XX offspring. Such sex-specific epi-marks are sexually antagonistic (SA-epi-marks) because they canalize sexual development in the parent that produced them, but contribute to gonad-trait discordances in opposite-sex offspring when unerased. In this model, homosexuality occurs when stronger-than-average SA-epi-marks (influencing sexual preference) from an opposite-sex parent escape erasure and are then paired with a weaker-than-average de novo sex-specific epi-marks produced in opposite-sex offspring. Our model predicts that homosexuality is part of a wider phenomenon in which recently evolved androgen-influenced traits commonly display gonad-trait discordances at substantial frequency, and that the molecular feature underlying most homosexuality is not DNA polymorphism(s), but epi-marks that evolved to canalize sexual dimorphic development that sometimes carryover across generations and contribute to gonad-trait discordances in opposite-sex descendants.]]> Tue, 12 Feb 2013 00:00:00 PST Seok J, Warren HS, Cuenca AG, Mindrinos MN, Baker HV, Xu W, Richards DR, McDonald-Smith GP, Gao H, Hennessy L, Finnerty CC, Lopez CM, Honari S, Moore EE, Minei JP, Cuschieri J, Bankey PE, Johnson JL, Sperry J, Nathens AB, Billiar TR, West MA, Jeschke MG, Klein MB, Gamelli RL, Gibran NS, Brownstein BH, Miller-Graziano C, Calvano SE, Mason PH, Cobb JP, Rahme LG, Lowry SF, Maier RV, Moldawer LL, Herndon DN, Davis RW, Xiao W, Tompkins RG
Proc Natl Acad Sci U S A (Feb 2013)

A cornerstone of modern biomedical research is the use of mouse models to explore basic pathophysiological mechanisms, evaluate new therapeutic approaches, and make go or no-go decisions to carry new drug candidates forward into clinical trials. Systematic studies evaluating how well murine models mimic human inflammatory diseases are nonexistent. Here, we show that, although acute inflammatory stresses from different etiologies result in highly similar genomic responses in humans, the responses in corresponding mouse models correlate poorly with the human conditions and also, one another. Among genes changed significantly in humans, the murine orthologs are close to random in matching their human counterparts (e.g., R(2) between 0.0 and 0.1). In addition to improvements in the current animal model systems, our study supports higher priority for translational medical research to focus on the more complex human conditions rather than relying on mouse models to study human inflammatory diseases.]]> Tue, 12 Feb 2013 00:00:00 PST Ehlert T, Simon P, Moser DA
Sports Med (Feb 2013)

The heritability of specific phenotypical traits relevant for physical performance has been extensively investigated and discussed by experts from various research fields. By deciphering the complete human DNA sequence, the human genome project has provided impressive insights into the genomic landscape. The hope that this information would reveal the origin of phenotypical traits relevant for physical performance or disease risks has proven overly optimistic, and it is still premature to refer to a 'post-genomic' era of biological science. Linking genomic regions with functions, phenotypical traits and variation in disease risk is now a major experimental bottleneck. The recent deluge of genome-wide association studies (GWAS) generates extensive lists of sequence variants and genes potentially linked to phenotypical traits, but functional insight is at best sparse. The focus of this review is on the complex mechanisms that modulate gene expression. A large fraction of these mechanisms is integrated into the field of epigenetics, mainly DNA methylation and histone modifications, which lead to persistent effects on the availability of DNA for transcription. With the exceptions of genomic imprinting and very rare cases of epigenetic inheritance, epigenetic modifications are not inherited transgenerationally. Along with their susceptibility to external influences, epigenetic patterns are highly specific to the individual and may represent pivotal control centers predisposing towards higher or lower physical performance capacities. In that context, we specifically review how epigenetics combined with classical genetics could broaden our knowledge of genotype-phenotype interactions. We discuss some of the shortcomings of GWAS and explain how epigenetic influences can mask the outcome of quantitative genetic studies. We consider epigenetic influences, such as genomic imprinting and epigenetic inheritance, as well as the life-long variability of epigenetic modification patterns and their potential impact on phenotype with special emphasis on traits related to physical performance. We suggest that epigenetic effects may also play a considerable role in the determination of athletic potential and these effects will need to be studied using more sophisticated quantitative genetic models. In the future, epigenetic status and its potential influence on athletic performance will have to be considered, explored and validated using well controlled model systems before we can begin to extrapolate new findings to complex and heterogeneous human populations. A combination of the fields of genomics, epigenomics and transcriptomics along with improved bioinformatics tools and precise phenotyping, as well as a precise classification of the test populations is required for future research to better understand the inter-relations of exercise physiology, performance traits and also susceptibility towards diseases. Only this combined input can provide the overall outlook necessary to decode the molecular foundation of physical performance.]]> Thu, 24 Jan 2013 00:00:00 PST Williams C, Hoppe HJ, Rezgui D, Strickland M, Forbes BE, Grutzner F, Frago S, Ellis RZ, Wattana-Amorn P, Prince SN, Zaccheo OJ, Nolan CM, Mungall AJ, Jones EY, Crump MP, Hassan AB
Science (Nov 2012)

Placental development and genomic imprinting coevolved with parental conflict over resource distribution to mammalian offspring. The imprinted genes IGF2 and IGF2R code for the growth promoter insulin-like growth factor 2 (IGF2) and its inhibitor, mannose 6-phosphate (M6P)/IGF2 receptor (IGF2R), respectively. M6P/IGF2R of birds and fish do not recognize IGF2. In monotremes, which lack imprinting, IGF2 specifically bound M6P/IGF2R via a hydrophobic CD loop. We show that the DNA coding the CD loop in monotremes functions as an exon splice enhancer (ESE) and that structural evolution of binding site loops (AB, HI, FG) improved therian IGF2 affinity. We propose that ESE evolution led to the fortuitous acquisition of IGF2 binding by M6P/IGF2R that drew IGF2R into parental conflict; subsequent imprinting may then have accelerated affinity maturation.]]> Fri, 30 Nov 2012 00:00:00 PST Fingerman IM, Zhang X, Ratzat W, Husain N, Cohen RF, Schuler GD
Nucleic Acids Res (Nov 2012)

The Epigenomics resource at the National Center for Biotechnology Information (NCBI) has been created to serve as a comprehensive public repository for whole-genome epigenetic data sets (www.ncbi.nlm.nih.gov/epigenomics). We have constructed this resource by selecting the subset of epigenetics-specific data from the Gene Expression Omnibus (GEO) database and then subjecting them to further review and annotation. Associated data tracks can be viewed using popular genome browsers or downloaded for local analysis. We have performed extensive user testing throughout the development of this resource, and new features and improvements are continuously being implemented based on the results. We have made substantial usability improvements to user interfaces, enhanced functionality, made identification of data tracks of interest easier and created new tools for preliminary data analyses. Additionally, we have made efforts to enhance the integration between the Epigenomics resource and other NCBI databases, including the Gene database and PubMed. Data holdings have also increased dramatically since the initial publication describing the NCBI Epigenomics resource and currently consist of >3700 viewable and downloadable data tracks from 955 biological sources encompassing five well-studied species. This updated manuscript highlights these changes and improvements.]]> Thu, 29 Nov 2012 00:00:00 PST Lim AL, Ng S, Leow SC, Choo R, Ito M, Chan YH, Goh SK, Tng E, Kwek K, Chong YS, Gluckman PD, Ferguson-Smith AC
J Med Genet (Nov 2012)

Genomic imprinting is a process causing genes to be expressed according to parental origin. Imprinting acts to coordinate fetal and prenatal growth, as well as control postnatal adaptations. Studies on human imprinting are confounded by tissue availability, sampling variability and limitations posed by tissue-specific expression and cellular heterogeneity within tissues. The human umbilical cord is an easily available, embryonic-derived fetal tissue with the potential to overcome many of these limitations.]]> Mon, 05 Nov 2012 00:00:00 PST Bernal AJ, Dolinoy DC, Huang D, Skaar DA, Weinhouse C, Jirtle RL
FASEB J (Nov 2013)

Humans are exposed to low-dose ionizing radiation (LDIR) from a number of environmental and medical sources. In addition to inducing genetic mutations, there is concern that LDIR may also alter the epigenome. Such heritable effects early in life can either be positively adaptive or result in the enhanced formation of diseases, including cancer, diabetes, and obesity. Herein, we show that LDIR significantly increased DNA methylation at the viable yellow agouti (A(vy)) locus in a sex-specific manner (P=0.004). Average DNA methylation was significantly increased in male offspring exposed to doses between 0.7 and 7.6 cGy, with maximum effects at 1.4 and 3.0 cGy (P<0.01). Offspring coat color was concomitantly shifted toward pseudoagouti (P<0.01). Maternal dietary antioxidant supplementation mitigated both the DNA methylation changes and coat color shift in the irradiated offspring. Thus, LDIR exposure during gestation elicits epigenetic alterations that lead to positive adaptive phenotypic changes that are negated with antioxidants, indicating they are mediated in part by oxidative stress. These findings provide evidence that in the isogenic A(vy) mouse model, epigenetic alterations resulting from LDIR play a role in radiation hormesis, bringing into question the assumption that every dose of radiation is harmful.-Bernal, A. J., Dolinoy, D. C., Huang, D., Skaar, D. A., Weinhouse, C., Jirtle, R. J. Adaptive radiation-induced epigenetic alterations mitigated by antioxidants.]]> Fri, 02 Nov 2012 00:00:00 PDT Prickett AR, Oakey RJ
Mol Genet Genomics (Aug 2012)

In mammals, most somatic cells contain two copies of each autosomal gene, one inherited from each parent. When a gene is expressed, both parental alleles are usually transcribed. However, a subset of genes is subject to the epigenetic silencing of one of the parental copies by genomic imprinting. In this review, we explore the evidence for variability in genomic imprinting between different tissue and cell types. We also consider why the imprinting of particular genes may be restricted to, or lost in, specific tissues and discuss the potential for high-throughput sequencing technologies in facilitating the characterisation of tissue-specific imprinting and assaying the potentially functional variations in epigenetic marks.]]> Mon, 30 Jul 2012 00:00:00 PDT Liu Y, Murphy SK, Murtha AP, Fuemmeler BF, Schildkraut J, Huang Z, Overcash F, Kurtzberg J, Jirtle R, Iversen ES, Forman MR, Hoyo C
Epigenetics (Jul 2012)

Depressed mood in pregnancy has been linked to low birth weight (LBW, < 2,500 g), a risk factor for adult-onset chronic diseases in offspring. We examined maternal depressed mood in relation to birth weight and evaluated the role of DNA methylation at regulatory sequences of imprinted genes in this association. We measured depressed mood among 922 pregnant women using the CES-D scale and obtained birth weight data from hospital records. Using bisulfite pyrosequencing of cord blood DNA from 508 infants, we measured methylation at differentially methylated regions (DMRs) regulating imprinted genes IGF2/H19, DLK1/MEG3, MEST, PEG3, PEG10/SGCE, NNAT and PLAGL1. Multiple regression models were used to examine the relationship between depressed mood, birth weight and DMR methylation levels. Depressed mood was associated with a more that 3-fold higher risk of LBW, after adjusting for delivery mode, parity, education, cigarette smoking, folic acid use and preterm birth. The association may be more pronounced in offspring of black women and female infants. Compared with infants of women without depressed mood, infants born to women with severe depressed mood had a 2.4% higher methylation at the MEG3 DMR. Whereas LBW infants had 1.6% lower methylation at the IGF2 DMR, high birth weight (> 4,500 g) infants had 5.9% higher methylation at the PLAGL1 DMR compared with normal birth weight infants. Our findings confirm that severe maternal depressed mood in pregnancy is associated with LBW, and that MEG3 and IGF2 plasticity may play important roles.]]> Fri, 08 Jun 2012 00:00:00 PDT Daxinger L, Whitelaw E
Nat Rev Genet (Mar 2012)

It is known that information that is not contained in the DNA sequence - epigenetic information - can be inherited from the parent to the offspring. However, many questions remain unanswered regarding the extent and mechanisms of such inheritance. In this Review, we consider the evidence for transgenerational epigenetic inheritance via the gametes, including cases of environmentally induced epigenetic changes. The molecular basis of this inheritance remains unclear, but recent evidence points towards diffusible factors, in particular RNA, rather than DNA methylation or chromatin. Interestingly, many cases of epigenetic inheritance seem to involve repeat sequences.]]> Mon, 20 Feb 2012 00:00:00 PST Onyango P, Feinberg AP
Proc Natl Acad Sci U S A (Oct 2011)

The H19 gene, which localizes within a chromosomal region on human chromosome 11p15 that is commonly lost in Wilms tumor (WT), encodes an imprinted untranslated RNA. However, the biological significance of the H19 noncoding transcript remains unresolved because replacement of the RNA transcript with a neocassette has no obvious phenotypic effect. Here we show that the human H19 locus also encodes a maternally expressed, translated gene, antisense to the known H19 transcript, which is conserved in primates. This gene, termed HOTS for H19 opposite tumor suppressor, encodes a protein that localizes to the nucleus and nucleolus and that interacts with the human enhancer of rudimentary homolog (ERH) protein. WTs that show loss of heterozygosity of 11p15 or loss of imprinting of IGF2 also silence HOTS (7/7 and 10/10, respectively). Overexpression of HOTS inhibits Wilms, rhabdoid, rhabdomyosarcoma, and choriocarcinoma tumor cell growth, and silencing HOTS by RNAi increases in vitro colony formation and in vivo tumor growth. These results demonstrate that the human H19 locus harbors an imprinted gene encoding a tumor suppressor protein within the long-sought WT2 locus.]]> Tue, 04 Oct 2011 21:00:00 PDT Ito S, Shen L, Dai Q, Wu SC, Collins LB, Swenberg JA, He C, Zhang Y
Science (Sep 2011)

5-methylcytosine (5mC) in DNA plays an important role in gene expression, genomic imprinting, and suppression of transposable elements. 5mC can be converted to 5-hydroxymethylcytosine (5hmC) by the Tet (ten eleven translocation) proteins. Here, we show that, in addition to 5hmC, the Tet proteins can generate 5-formylcytosine (5fC) and 5-carboxylcytosine (5caC) from 5mC in an enzymatic activity-dependent manner. Furthermore, we reveal the presence of 5fC and 5caC in genomic DNA of mouse embryonic stem cells and mouse organs. The genomic content of 5hmC, 5fC, and 5caC can be increased or reduced through overexpression or depletion of Tet proteins. Thus, we identify two previously unknown cytosine derivatives in genomic DNA as the products of Tet proteins. Our study raises the possibility that DNA demethylation may occur through Tet-catalyzed oxidation followed by decarboxylation.]]> Fri, 02 Sep 2011 00:00:00 PDT Ferron SR, Charalambous M, Radford E, McEwen K, Wildner H, Hind E, Morante-Redolat JM, Laborda J, Guillemot F, Bauer SR, Farinas I, Ferguson-Smith AC
Nature (Jul 2011)

The gene for the atypical NOTCH ligand delta-like homologue 1 (Dlk1) encodes membrane-bound and secreted isoforms that function in several developmental processes in vitro and in vivo. Dlk1, a member of a cluster of imprinted genes, is expressed from the paternally inherited chromosome. Here we show that mice that are deficient in Dlk1 have defects in postnatal neurogenesis in the subventricular zone: a developmental continuum that results in depletion of mature neurons in the olfactory bulb. We show that DLK1 is secreted by niche astrocytes, whereas its membrane-bound isoform is present in neural stem cells (NSCs) and is required for the inductive effect of secreted DLK1 on self-renewal. Notably, we find that there is a requirement for Dlk1 to be expressed from both maternally and paternally inherited chromosomes. Selective absence of Dlk1 imprinting in both NSCs and niche astrocytes is associated with postnatal acquisition of DNA methylation at the germ-line-derived imprinting control region. The results emphasize molecular relationships between NSCs and the niche astrocyte cells of the microenvironment, identifying a signalling system encoded by a single gene that functions coordinately in both cell types. The modulation of genomic imprinting in a stem-cell environment adds a new level of epigenetic regulation to the establishment and maintenance of the niche, raising wider questions about the adaptability, function and evolution of imprinting in specific developmental contexts.]]> Thu, 21 Jul 2011 00:00:00 PDT Ferguson-Smith AC
Nat Rev Genet (Aug 2011)

The emerging awareness of the contribution of epigenetic processes to genome function in health and disease is underpinned by decades of research in model systems. In particular, many principles of the epigenetic control of genome function have been uncovered by studies of genomic imprinting. The phenomenon of genomic imprinting, which results in some genes being expressed in a parental--origin-specific manner, is essential for normal mammalian growth and development and exemplifies the regulatory influences of DNA methylation, chromatin structure and non-coding RNA. Setting seminal discoveries in this field alongside recent progress and remaining questions shows how the study of imprinting continues to enhance our understanding of the epigenetic control of genome function in other contexts.]]> Mon, 18 Jul 2011 00:00:00 PDT Buiting K, Kanber D, Horsthemke B, Lohmann D
Brief Funct Genomics (Jul 2010)

Recent data have revealed that the paradigmatic tumour suppressor gene RB1 on chromosome 13 is preferentially expressed from the maternal allele. Imprinted expression of RB1 is linked to a differentially methylated CpG island in intron 2 of this gene (CpG 85). On the paternal chromosome, CpG 85 is unmethylated and acts as a weak promoter of an alternative RB1 transcript. Paternal mRNA levels are probably reduced as the result of transcriptional interference of the regular promoter and the alternative promoter on this chromosome. CpG 85 is part of a truncated processed pseudogene (KIAA0649P) that integrated into the RB1 gene prior to the speciation of extant primates. It is plausible that differential penetrance and variation of age at diagnosis, which have been observed in patients with hereditary and non-hereditary retinoblastoma, respectively, are a consequence of imprinted expression of the RB1 gene. Interestingly, RB1 is imprinted in the same direction as CDKN1C, which operates upstream of RB1. The imprinting of two components of the same pathway indicates that there has been strong evolutionary selection for maternal inhibition of cell proliferation.]]> Mon, 02 Aug 2010 00:00:00 PDT Ubeda F, Gardner A
Evolution (Apr 2010)

What are imprinted genes doing in the adult brain? Genomic imprinting is when a gene's expression depends upon parent of origin. According to the prevailing view, the "kinship theory" of genomic imprinting, this effect is driven by evolutionary conflicts between genes inherited via sperm versus egg. This theory emphasizes conflicts over the allocation of maternal resources, and focuses upon genes that are expressed in the placenta and infant brain. However, there is growing evidence that imprinted genes are also expressed in the juvenile and adult brain, after cessation of parental care. These genes have recently been suggested to underpin neurological disorders of the social brain such as psychosis and autism. Here we advance the kinship theory by developing an evolutionary model of genomic imprinting for social behavior beyond the nuclear family. We consider the role of demography and mating system, emphasizing the importance of sex differences in dispersal and variance in reproductive success. We predict that, in hominids and birds, altruism will be promoted by paternally inherited genes and egoism will be promoted by maternally inherited genes. In nonhominid mammals we predict more diversity, with some mammals showing the same pattern and other showing the reverse. We discuss the implications for the evolution of psychotic and autistic spectrum disorders in human populations with different social structures.]]> Tue, 25 May 2010 21:00:00 PDT Okada Y, Yamagata K, Hong K, Wakayama T, Zhang Y
Nature (Jan 2010)

The life cycle of mammals begins when a sperm enters an egg. Immediately after fertilization, both the maternal and paternal genomes undergo dramatic reprogramming to prepare for the transition from germ cell to somatic cell transcription programs. One of the molecular events that takes place during this transition is the demethylation of the paternal genome. Despite extensive efforts, the factors responsible for paternal DNA demethylation have not been identified. To search for such factors, we developed a live cell imaging system that allows us to monitor the paternal DNA methylation state in zygotes. Through short-interfering-RNA-mediated knockdown in mouse zygotes, we identified Elp3 (also called KAT9), a component of the elongator complex, to be important for paternal DNA demethylation. We demonstrate that knockdown of Elp3 impairs paternal DNA demethylation as indicated by reporter binding, immunostaining and bisulphite sequencing. Similar results were also obtained when other elongator components, Elp1 and Elp4, were knocked down. Importantly, injection of messenger RNA encoding the Elp3 radical SAM domain mutant, but not the HAT domain mutant, into MII oocytes before fertilization also impaired paternal DNA demethylation, indicating that the SAM radical domain is involved in the demethylation process. Our study not only establishes a critical role for the elongator complex in zygotic paternal genome demethylation, but also indicates that the demethylation process may be mediated through a reaction that requires an intact radical SAM domain.]]> Thu, 28 Jan 2010 21:00:00 PST Bischoff SR, Tsai S, Hardison N, Motsinger-Reif AA, Freking BA, Nonneman D, Rohrer G, Piedrahita JA
Biol Reprod (Nov 2009)

To increase our understanding of imprinted genes in swine, we carried out a comprehensive analysis of this gene family using two complementary approaches: expression and phenotypic profiling of parthenogenetic fetuses, and analysis of imprinting by pyrosequencing. The parthenote placenta and fetus were smaller than those of controls but had no obvious morphological differences at Day 28 of gestation. By Day 30, however, the parthenote placentas had decreased chorioallantoic folding, decreased chorionic ruggae, and reduction of fetal-maternal interface surface in comparison with stage-matched control fetuses. Using Affymetrix Porcine GeneChip microarrays and/or semiquantitative PCR, brain, fibroblast, liver, and placenta of Day 30 fetuses were profiled, and 25 imprinted genes were identified as differentially expressed in at least one of the four tissue types: AMPD3, CDKN1C, COPG2, DHCR7, DIRAS3, IGF2 (isoform specific), IGF2AS, IGF2R, MEG3, MEST, NAP1L5, NDN, NNAT, OSBPL1A, PEG3, APEG3, PEG10, PLAGL1, PON2, PPP1R9A, SGCE, SLC38A4, SNORD107, SNRPN, and TFPI2. For DIRAS3, PLAGL1, SGCE, and SLC38A4, tissue-specific differences were detected. In addition, we examined the imprinting status of candidate genes by quantitative allelic pyrosequencing. Samples were collected from Day 30 pregnancies generated from reciprocal crosses of Meishan and White Composite breeds, and single-nucleotide polymorphisms were identified in candidate genes. Imprinting was confirmed for DIRAS3, DLK1, H19, IGF2AS, NNAT, MEST, PEG10, PHLDA2, PLAGL1, SGCE, and SNORD107. We also found no evidence of imprinting in ASB4, ASCL2, CD81, COMMD1, DCN, DLX5, and H13. Combined, these results represent the most comprehensive survey of imprinted genes in swine to date.]]> Wed, 28 Oct 2009 21:00:00 PDT Dindot SV, Person R, Strivens M, Garcia R, Beaudet AL
Genome Res (Jun 2009)

Genomic imprinting arises from allele-specific epigenetic modifications that are established during gametogenesis and that are maintained throughout somatic development. These parental-specific modifications include DNA methylation and post-translational modifications to histones, which create allele-specific active and repressive domains at imprinted regions. Through the use of a high-density genomic tiling array, we generated DNA and histone methylation profiles at 11 imprinted gene clusters in the mouse from DNA and from chromatin immunoprecipitated from sperm, heart, and cerebellum. Our analysis revealed that despite high levels of differential DNA methylation at non-CpG islands within these regions, imprinting control regions (ICRs) and secondary differentially methylated regions (DMRs) were identified by an overlapping pattern of H3K4 trimethylation (active chromatin) and H3K9 trimethylation (repressive chromatin) modifications in somatic tissue, and a sperm differentially methylated region (sDMR; sperm not equal somatic tissue). Using these features as a common signature of DMRs, we identified 11 unique regions that mapped to known imprinted genes, to uncharacterized genes, and to intergenic regions flanking known imprinted genes. A common feature among these regions was the presence of a CpG island and an array of tandem repeats. Collectively, this study provides a comprehensive analysis of DNA methylation and histone H3K4me3 and H3K9me3 modifications at imprinted gene clusters, and identifies common epigenetic and genetic features of regions regulating genomic imprinting.]]> Sun, 21 Jun 2009 21:00:00 PDT Zeh DW, Zeh JA, Ishida Y
Bioessays (Jul 2009)

Evolution is frequently concentrated in bursts of rapid morphological change and speciation followed by long-term stasis. We propose that this pattern of punctuated equilibria results from an evolutionary tug-of-war between host genomes and transposable elements (TEs) mediated through the epigenome. According to this hypothesis, epigenetic regulatory mechanisms (RNA interference, DNA methylation and histone modifications) maintain stasis by suppressing TE mobilization. However, physiological stress, induced by climate change or invasion of new habitats, disrupts epigenetic regulation and unleashes TEs. With their capacity to drive non-adaptive host evolution, mobilized TEs can restructure the genome and displace populations from adaptive peaks, thus providing an escape from stasis and generating genetic innovations required for rapid diversification. This \"epi-transposon hypothesis\" can not only explain macroevolutionary tempo and mode, but may also resolve other long-standing controversies, such as Wright\'s shifting balance theory, Mayr\'s peripheral isolates model, and McClintock\'s view of genome restructuring as an adaptive response to challenge.]]> Tue, 16 Jun 2009 21:00:00 PDT Sharma A, Singh P
PLoS ONE (Jan 2009)

Available instances of inheritance of epigenetic transgenerational phenotype are limited to environmental exposures during embryonic and adult gonadal development. Adult exposures can also affect gametogenesis and thereby potentially result in reprogramming of the germline. Although examples of epigenetic effects on gametogenesis exist, it is notable that transgenerational inheritance of environment-induced adult phenotype has not yet been reported. Epigenetic codes are considered to be critical in neural plasticity. A Drosophila systems model of pentylenetetrazole (PTZ) induced long-term brain plasticity has recently been described. In this model, chronic PTZ treatment of adult males causes alterations in CNS transcriptome. Here, we describe our search for transgenerational spermatogenic inheritance of PTZ induced gene expression phenotype acquired by adult Drosophila males. We generated CNS transcriptomic profiles of F(1) adults after treating F(0) adult males with PTZ and of F(2) adults resulting from a cross between F(1) males and normal females. Surprisingly, microarray clustering showed F(1) male profile as closest to F(1) female and F(0) male profile closest to F(2) male. Differentially expressed genes in F(1) males, F(1) females and F(2) males showed significant overlap with those caused by PTZ. Interestingly, microarray evidence also led to the identification of upregulated rRNA in F(2) males. Next, we generated microarray expression profiles of adult testis from F(0) and F(1) males. Further surprising, clustering of CNS and testis profiles and matching of differentially expressed genes in them provided evidence of a spermatogenic mechanism in the transgenerational effect observed. To our knowledge, we report for the first time detection of transgenerational spermatogenic inheritance of adult acquired somatic gene expression characteristic. The Drosophila systems model offers an excellent opportunity to understand the epigenetic mechanisms underlying the phenomenon. The finding that adult acquired transcriptomic alteration in soma is spermatogenically inherited across generations has potential implications in human health and evolution.]]> Sun, 07 Jun 2009 21:00:00 PDT McGowan PO, Sasaki A, D'Alessio AC, Dymov S, Labonte B, Szyf M, Turecki G, Meaney MJ
Nat Neurosci (Mar 2009)

Maternal care influences hypothalamic-pituitary-adrenal (HPA) function in the rat through epigenetic programming of glucocorticoid receptor expression. In humans, childhood abuse alters HPA stress responses and increases the risk of suicide. We examined epigenetic differences in a neuron-specific glucocorticoid receptor (NR3C1) promoter between postmortem hippocampus obtained from suicide victims with a history of childhood abuse and those from either suicide victims with no childhood abuse or controls. We found decreased levels of glucocorticoid receptor mRNA, as well as mRNA transcripts bearing the glucocorticoid receptor 1F splice variant and increased cytosine methylation of an NR3C1 promoter. Patch-methylated NR3C1 promoter constructs that mimicked the methylation state in samples from abused suicide victims showed decreased NGFI-A transcription factor binding and NGFI-A-inducible gene transcription. These findings translate previous results from rat to humans and suggest a common effect of parental care on the epigenetic regulation of hippocampal glucocorticoid receptor expression.]]> Wed, 25 Feb 2009 21:00:00 PST Bliek J, Verde G, Callaway J, Maas SM, De Crescenzo A, Sparago A, Cerrato F, Russo S, Ferraiuolo S, Rinaldi MM, Fischetto R, Lalatta F, Giordano L, Ferrari P, Cubellis MV, Larizza L, Temple IK, Mannens MM, Mackay DJ, Riccio A
Eur J Hum Genet (Dec 2008)

Genomic imprinting is an epigenetic phenomenon restricting gene expression in a manner dependent on parent of origin. Imprinted gene products are critical regulators of growth and development, and imprinting disorders are associated with both genetic and epigenetic mutations, including disruption of DNA methylation within the imprinting control regions (ICRs) of these genes. It was recently reported that some patients with imprinting disorders have a more generalised imprinting defect, with hypomethylation at a range of maternally methylated ICRs. We report a cohort of 149 patients with a clinical diagnosis of Beckwith-Wiedemann syndrome (BWS), including 81 with maternal hypomethylation of the KCNQ1OT1 ICR. Methylation analysis of 11 ICRs in these patients showed that hypomethylation affecting multiple imprinted loci was restricted to 17 patients with hypomethylation of the KCNQ1OT1 ICR, and involved only maternally methylated loci. Both partial and complete hypomethylation was demonstrated in these cases, suggesting a possible postzygotic origin of a mosaic imprinting error. Some ICRs, including the PLAGL1 and GNAS/NESPAS ICRs implicated in the aetiology of transient neonatal diabetes and pseudohypoparathyroidism type 1b, respectively, were more frequently affected than others. Although we did not find any evidence for mutation of the candidate gene DNMT3L, these results support the hypotheses that trans-acting factors affect the somatic maintenance of imprinting at multiple maternally methylated loci and that the clinical presentation of these complex cases may reflect the loci and tissues affected with the epigenetic abnormalities.European Journal of Human Genetics advance online publication, 17 December 2008; doi:10.1038/ejhg.2008.233.]]> Wed, 17 Dec 2008 21:00:00 PST Jirtle RL
Pharmacogenomics (Dec 2008)

Randy L Jirtle is a Professor of Radiation Oncology and an Associate Professor of Pathology at Duke University, Durham (NC, USA) where he has been a faculty member since 1977. He graduated with a BS degree in nuclear engineering in 1970 and a PhD degree in radiation biology in 1976, both from the University of Wisconsin-Madison. Jirtle\'s research interests are in epigenetics, genomic imprinting, and the fetal origins of disease susceptibility. He has published more than 160 peer-reviewed articles, including ten publications featured on journal covers. His enthusiasm for promoting the public understanding of epigenomics led him to create the website, www.geneimprint.org , which has been designated by the scientific publisher Thomson ISI as an \'Exemplary Website in Genetics\'. Jirtle has organized five international meetings and been an invited speaker at dozens of others. He has delivered five endowed lectures and was invited to present his research at the 2004 Nobel Symposium on Epigenetics. He was honored in 2006 with the Distinguished Achievement Award from the College of Engineering at the University of Wisconsin-Madison. In 2007, Jirtle received an Esther B. O\'Keeffe Charitable Foundation Award and capped off the year with a nomination for Time Magazine\'s \'Person of the Year\'. He was the inaugural recipient of the Epigenetic Medicine Award in 2008.]]> Mon, 15 Dec 2008 21:00:00 PST Badcock C, Crespi B
Nature (Aug 2008)

]]> Thu, 28 Aug 2008 21:00:00 PDT Fu VX, Dobosy JR, Desotelle JA, Almassi N, Ewald JA, Srinivasan R, Berres M, Svaren J, Weindruch R, Jarrard DF
Cancer Res (Aug 2008)

Loss of imprinting (LOI) is an epigenetic alteration involving loss of parental origin-specific expression at normally imprinted genes. A LOI for Igf2, a paracrine growth factor, is important in cancer progression. Epigenetic modifications may be altered by environmental factors. However, is not known whether changes in imprinting occur with aging in prostate and other tissues susceptible to cancer development. We found a LOI for Igf2 occurs specifically in the mouse prostate associated with increased Igf2 expression during aging. In older animals, expression of the chromatin insulator protein CTCF and its binding to the Igf2-H19 imprint control region was reduced. Forced down-regulation of CTCF leads to Igf2 LOI. We further show that Igf2 LOI occurs with aging in histologically normal human prostate tissues and that this epigenetic alteration was more extensive in men with associated cancer. This finding may contribute to a postulated field of cancer susceptibility that occurs with aging. Moreover, Igf2 LOI may serve as a marker for the presence of prostate cancer.]]> Wed, 13 Aug 2008 21:00:00 PDT  American Association for Cancer Research Human Epigenome Task Force; European Union, Network of Excellence, Scientific Advisory Board
Nature (Aug 2008)

]]> Wed, 06 Aug 2008 21:00:00 PDT Smits G, Mungall AJ, Griffiths-Jones S, Smith P, Beury D, Matthews L, Rogers J, Pask AJ, Shaw G, VandeBerg JL, McCarrey JR, Renfree MB, Reik W, Dunham I
Nat Genet (Aug 2008)

Comparisons between eutherians and marsupials suggest limited conservation of the molecular mechanisms that control genomic imprinting in mammals. We have studied the evolution of the imprinted IGF2-H19 locus in therians. Although marsupial orthologs of protein-coding exons were easily identified, the use of evolutionarily conserved regions and low-stringency Bl2seq comparisons was required to delineate a candidate H19 noncoding RNA sequence. The therian H19 orthologs show miR-675 and exon structure conservation, suggesting functional selection on both features. Transcription start site sequences and poly(A) signals are also conserved. As in eutherians, marsupial H19 is maternally expressed and paternal methylation upstream of the gene originates in the male germline, encompasses a CTCF insulator, and spreads somatically into the H19 gene. The conservation in all therians of the mechanism controlling imprinting of the IGF2-H19 locus suggests a sequential model of imprinting evolution.]]> Tue, 29 Jul 2008 21:00:00 PDT Zeh JA, Zeh DW
Ann N Y Acad Sci (Jun 2008)

Equipped with Mendel\'s laws and only rudimentary knowledge of genes and genomes, the architects of the Modern Synthesis provided key insights into the dynamics of gene frequency change within populations. Extension of population genetic models to speciation identified Dobzhansky-Muller incompatibilities (negative epistatic interactions between genes from isolated populations) as the primary cause of hybrid inviability and sterility, a view consistent with empirical findings on the genetics of reproductive isolation in Drosophila. Although speciation models have become increasingly mathematically sophisticated, many remain based on an overly static concept of the genome, grounded in Mendelian genetics and devoid of potentially important biological details. A unifying theory of speciation therefore remains elusive, with debate over the relative importance of natural selection, sexual selection, sexual conflict, genetic drift, and selfish genetic elements in the evolution of reproductive isolation. Drawing on recent findings in molecular genetics and comparative genomics, we revisit, update, and extend the theory that reproductive mode plays a crucial role in shaping the speciation process. By providing a direct conduit for manipulation of the mother\'s physiology by genes expressed in the embryo, viviparity creates a postfertilization arena for genomic conflicts absent in species that lay eggs. In polyandrous species, viviparity-driven conflict (VDC) is likely to generate perpetual antagonistic coevolution between genes expressed during embryonic development and those involved in maternal reproductive physiology, thereby accelerating the rate at which postzygotic isolation evolves between populations. Moreover, in mammals and flowering plants, VDC has favored the evolution of genomic imprinting and a central role for epigenetic mechanisms in the regulation of antagonistic patterns of gene expression by maternally and paternally inherited genomes. VDC can account for the rapid rate at which mammals and viviparous fishes lose their ability to hybridize; the key role of the triploid endosperm in postzygotic reproductive isolation in flowering plants; and the kinds of traits, genes, and gene regulatory systems most critical to the evolution of postzygotic reproductive isolation in live-bearing species.]]> Tue, 17 Jun 2008 21:00:00 PDT McGowan PO, Sasaki A, Huang TC, Unterberger A, Suderman M, Ernst C, Meaney MJ, Turecki G, Szyf M
PLoS ONE (Jan 2008)

BACKGROUND: Alterations in gene expression in the suicide brain have been reported and for several genes DNA methylation as an epigenetic regulator is thought to play a role. rRNA genes, that encode ribosomal RNA, are the backbone of the protein synthesis machinery and levels of rRNA gene promoter methylation determine rRNA transcription. METHODOLOGY/PRINCIPAL FINDINGS: We test here by sodium bisulfite mapping of the rRNA promoter and quantitative real-time PCR of rRNA expression the hypothesis that epigenetic differences in critical loci in the brain are involved in the pathophysiology of suicide. Suicide subjects in this study were selected for a history of early childhood neglect/abuse, which is associated with decreased hippocampal volume and cognitive impairments. rRNA was significantly hypermethylated throughout the promoter and 5\\\' regulatory region in the brain of suicide subjects, consistent with reduced rRNA expression in the hippocampus. This difference in rRNA methylation was not evident in the cerebellum and occurred in the absence of genome-wide changes in methylation, as assessed by nearest neighbor. CONCLUSIONS/SIGNIFICANCE: This is the first study to show aberrant regulation of the protein synthesis machinery in the suicide brain. The data implicate the epigenetic modulation of rRNA in the pathophysiology of suicide.]]> Tue, 06 May 2008 21:00:00 PDT Kuehn BM
JAMA (Mar 2008)

]]> Mon, 31 Mar 2008 12:45:46 PDT Menheniott TR, Woodfine K, Schulz R, Wood AJ, Monk D, Giraud AS, Baldwin HS, Moore GE, Oakey RJ
Mol Cell Biol (Jan 2008)

By combining a tissue-specific microarray screen with mouse uniparental duplications, we have identified a novel imprinted gene, Dopa decarboxylase (Ddc), on chromosome 11. Ddc_exon1a is a 2-kb transcript variant that initiates from an alternative first exon in intron 1 of the canonical Ddc transcript and is paternally expressed in trabecular cardiomyocytes of the embryonic and neonatal heart. Ddc displays tight conserved linkage with the maternally expressed and methylated Grb10 gene, suggesting that these reciprocally imprinted genes may be coordinately regulated. In Dnmt3L mutant embryos that lack maternal germ line methylation imprints, we show that Ddc is overexpressed and Grb10 is silenced. Their imprinting is therefore dependent on maternal germ line methylation, but the mechanism at Ddc does not appear to involve differential methylation of the Ddc_exon1a promoter region and may instead be provided by the oocyte mark at Grb10. Our analysis of Ddc redefines the imprinted Grb10 domain on mouse proximal chromosome 11 and identifies Ddc_exon1a as the first example of a heart-specific imprinted gene.]]> Tue, 18 Dec 2007 21:00:00 PST Luedi PE, Dietrich FS , Weidman JR, Bosko JM, Jirtle RL, Hartemink AJ
Genome Res. (Dec 2007)

Imprinted genes are essential in embryonic development, and imprinting dysregulation contributes to human disease. We report two new human imprinted genes: KCNK9 is predominantly expressed in the brain, is a known oncogene, and may be involved in bipolar disorder and epilepsy, while DLGAP2 is a candidate bladder cancer tumor suppressor. Both genes lie on chromosome 8, not previously suspected to contain imprinted genes. We identified these genes,along with 154 others, based on the predictions of multiple classification algorithms using DNA sequence characteristics as features. Our findings demonstrate that DNA sequence characteristics, including recombination hot spots, are sufficient to accurately predict the imprinting status of individual genes in the human genome.]]> Fri, 30 Nov 2007 21:44:13 PST Miranda TB, Jones PA
J Cell Physiol (Nov 2007)

DNA methylation is an epigenetic modification which plays an important role in chromatin organization and gene expression. DNA methylation can silence genes and repetitive elements through a process which leads to the alteration of chromatin structure. The mechanisms which target DNA methylation to specific sites in the genome are not fully understood. In this review, we will discuss the mechanisms which lead to the long-term silencing of genes and will survey the progression that has been made in determining the targeted mechanisms for de novo DNA methylation. J. Cell. Physiol. 213: 384-390, 2007. (c) 2007 Wiley-Liss, Inc.]]> Sun, 02 Sep 2007 21:00:00 PDT Hitchler MJ, Domann FE
Free Radic Biol Med (Oct 2007)

The development of organisms requires concerted changes in gene activity. The free radical theory of development proposes that oxygen serves as a morphogen to educe development by influencing the production of metabolic oxidants such as free radicals and reactive oxygen species. One of the central tenets of this theory is that these metabolic oxidants influence development by altering the antioxidant capacity of cells by changing their production of glutathione (GSH). Here we extend on these principles by linking GSH production and oxygen sensing in the control of gene expression to establish the epigenotype of cells during development. We prescribe this novel role to GSH and oxygen during development because these metabolites influence the activity of enzymes responsible for initiating and perpetuating epigenetic control of gene expression. Increased GSH production influences epigenetic processes including DNA and histone methylation by limiting the availability of S-adenosylmethionine, the cofactor utilized during epigenetic control of gene expression by DNA and histone methyltransferases. Moreover, the recent discovery of histone demethylases that require oxygen as a cofactor directly links epigenetic processes to oxygen gradients during development.]]> Thu, 30 Aug 2007 21:00:00 PDT Shimabukuro M, Sasaki T, Imamura A, Tsujita T, Fuke C, Umekage T, Tochigi M, Hiramatsu K, Miyazaki T, Oda T, Sugimoto J, Jinno Y, Okazaki Y
J Psychiatr Res (Dec 2007)

Genetic and epigenetic factors can potentially alter susceptibility to psychiatric disorders such as schizophrenia. In order to explore the effect of epigenetics on the pathogenesis of schizophrenia, we examined the global methylation level of leukocyte DNA from 210 patients with schizophrenia (124 males and 86 females) and 237 healthy subjects (108 males and 129 females). Methylated deoxycytidine (mC) content in peripheral leukocyte DNA was measured by high performance liquid chromatography (HPLC). We confirmed in the healthy subjects our previous finding that there are sex-dependent differences in mC content (males>females; beta=0.319, p<0.001), in addition to the effect of age (beta=-0.141, p=0.022). We therefore used multiple regression to analyze the data from all subjects by sex, with age as a co-variant. In males, a tendency was observed toward lower mC content in patients than in controls (beta=-0.115, p=0.075), with a significant effect of age (beta=-0.212, p<0.001). This difference was more prominent in younger individuals. In females, no effect of age or disease status on mC content was observed. These results established that there is significant sex-dependent difference in the mC content of human peripheral leukocyte DNA, and raise the possibility that alterations in DNA methylation state are present in patients with schizophrenia.]]> Mon, 27 Aug 2007 21:00:00 PDT Da Jia, D, Renata Z. Jurkowska, Xing Zhang1, , Albert Jeltsch, Xiaodong Cheng1
Nature (Aug 22)

]]> Thu, 23 Aug 2007 20:20:34 PDT Zaitseva I, Zaitsev S, Alenina N, Bader M, Krivokharchenko A
Mol Reprod Dev (Oct 2007)

Virtually all mammalian species including mouse, rat, pig, cow, and human, but not sheep and rabbit, undergo genome-wide epigenetic reprogramming by demethylation of the male pronucleus in early preimplantation development. In this study, we have investigated and compared the dynamics of DNA demethylation in preimplantation mouse and rat embryos by immunofluorescence staining with an antibody against 5-methylcytosine. We performed for the first time a detailed analysis of demethylation kinetics of early rat preimplantation embryos and have shown that active demethylation of the male pronucleus in rat zygotes proceeds with a slower kinetic than that in mouse embryos. Using dated mating we found that equally methylated male and female pronuclei were observed at 3 hr after copulation for mouse and 6 hr for rat embryos. However, a difference in methylation levels between male and female pronuclei could be observed already at 8 hr after copulation in mouse and 10 hr in rat. At 10 hr after copulation, mouse male pronuclei were completely demethylated, whereas rat zygotes at 16 hr after copulation still exhibited detectable methylation of the male pronucleus. In addition in both species, a higher DNA methylation level was found in embryos developed in vitro compared to in vivo, which may be one of the possible reasons for the described aberrations in embryonic gene expression after in vitro embryo manipulation and culture. Mol. Reprod. Dev. 74: 1255-1261, 2007. (c) 2007 Wiley-Liss, Inc.]]> Wed, 01 Aug 2007 21:00:00 PDT Waterland RA, Michels KB
Annu Rev Nutr (Aug 2007)

Extensive human epidemiologic and animal model data indicate that during critical periods of prenatal and postnatal mammalian development, nutrition and other environmental stimuli influence developmental pathways and thereby induce permanent changes in metabolism and chronic disease susceptibility. The biologic mechanisms underlying this "developmental origins hypothesis" are poorly understood. This review focuses on the likely involvement of epigenetic mechanisms in the developmental origins of health and disease (DOHaD). We describe permanent effects of transient environmental influences on the developmental establishment of epigenetic gene regulation and evidence linking epigenetic dysregulation with human disease. We propose a definition of "epigenetic epidemiology" and delineate how this emerging field provides a basis from which to explore the role of epigenetic mechanisms in DOHaD. We suggest strategies for future human epidemiologic studies to identify causal associations between early exposures, long-term changes in epigenetic regulation, and disease, which may ultimately enable specific early-life interventions to improve human health.]]> Tue, 31 Jul 2007 21:00:00 PDT Drake AJ, Tang JI, Nyirenda MJ
Clin Sci (Lond) (Sep 2007)

Compelling epidemiological evidence suggests that exposure to an adverse intrauterine environment, manifested by low-birth weight, is associated with cardiometabolic and behavioural disorders in adulthood. These observations have led to the concept of 'fetal programming'. The molecular mechanisms that underlie this relationship remain unclear, but are being extensively investigated using a number of experimental models. One major hypothesis for early life physiological programming implicates fetal overexposure to stress (glucocorticoid) hormones. Several animal studies have shown that prenatal glucocorticoid excess, either from endogenous overproduction with maternal stress or through exogenous administration to the mother or fetus, reduces birth weight and causes lifelong hypertension, hyperglycaemia and behavioural abnormality in the offspring. Intriguingly, these effects are transmitted across generations without further exposure to glucocorticoids, which suggests an epigenetic mechanism. These animal observations could have huge implications if extrapolated to humans, where glucocorticoids have extensive therapeutic use in obstetric and neonatal practice.]]> Mon, 30 Jul 2007 21:00:00 PDT Dolinoy DC, Huang D , Jirtle RL 
Proc. Natl. Acad. Sci. USA (Jul 2007)

The hypothesis of fetal origins of adult disease posits that early developmental exposures involve epigenetic modifications, such as DNA methylation, that influence adult disease susceptibility. In utero or neonatal exposure to bisphenol A (BPA), a high-production-volume chemical used in the manufacture of polycarbonate plastic, is associated with higher body weight, increased breast and prostate cancer, and altered reproductive function. This study shows that maternal exposure to this endocrine-active compound shifted the coat color distribution of viable yellow agouti (Avy) mouse offspring toward yellow by decreasing CpG methylation in an intracisternal A particle retrotransposon upstream of the Agouti gene. CpG methylation also was decreased at another metastable locus, the CDK5 activator-binding protein (CabpIAP). DNA methylation at the AvyAvy locus was similar in tissues from the three germ layers, providing evidence that epigenetic patterning during early stem cell development is sensitive to BPA exposure. Moreover, maternal dietary supplementation, with either methyl donors like folic acid or the phytoestrogen genistein, negated the DNA hypomethylating effect of BPA. Thus, we present compelling evidence that early developmental exposure to BPA can change offspring phenotype by stably altering the epigenome, an effect that can be counteracted by maternal dietary supplements. ]]> Sun, 29 Jul 2007 18:55:30 PDT Khatib H, Zaitoun I, Kim ES
Mamm Genome (Jul 2007)

Genomic imprinting is an epigenetic mechanism that results in monoallelic expression of genes depending on parent-of-origin of the allele. Although the conservation of genomic imprinting among mammalian species has been widely reported for many genes, there is accumulating evidence that some genes escape this conservation. Most known imprinted genes have been identified in the mouse and human, with few imprinted genes reported in cattle. Comparative analysis of genomic imprinting across mammalian species would provide a powerful tool for elucidating the mechanisms regulating the unique expression of imprinted genes. In this study we analyzed the imprinting of 22 genes in human, mouse, and cattle and found that in only 11 was imprinting conserved across the three species. In addition, we analyzed the occurrence of the sequence elements CpG islands, C + G content, tandem repeats, and retrotransposable elements in imprinted and in nonimprinted (control) cattle genes. We found that imprinted genes have a higher G + C content and more CpG islands and tandem repeats. Short interspersed nuclear elements (SINEs) were notably fewer in number in imprinted cattle genes compared to control genes, which is in agreement with previous reports for human and mouse imprinted regions. Long interspersed nuclear elements (LINEs) and long terminal repeats (LTRs) were found to be significantly underrepresented in imprinted genes compared to control genes, contrary to reports on human and mouse. Of considerable significance was the finding of highly conserved tandem repeats in nine of the genes imprinted in all three species.]]> Wed, 25 Jul 2007 21:00:00 PDT Kato Y, Kaneda M, Hata K, Kumaki K, Hisano M, Kohara Y, Okano M, Li E, Nozaki M, Sasaki H
Hum Mol Genet (Jul 2007)

DNA methylation is an important epigenetic modification regulating various biological phenomena, including genomic imprinting and transposon silencing. It is known that methylation of the differentially methylated regions (DMRs) associated with paternally imprinted genes and of some repetitive elements occurs during male germ cell development in the mouse. We have performed a detailed methylation analysis of the paternally methylated DMRs (H19, Dlk1/Gtl2 and Rasgrf1), interspersed repeats (SineB1, IAP and Line1) and satellite repeats (major and minor) to determine the timing of this de novo methylation in male germ cells. Furthermore, we have examined the roles of the de novo methyltransferases (Dnmt3a and Dnmt3b) and related protein (Dnmt3L) in this process. We found that methylation of all DMRs and repeats occurred progressively in fetal prospermatogonia and was completed by the newborn stage. Analysis of newborn prospermatogonia from germline-specific Dnmt3a and Dnmt3b knockout mice revealed that Dnmt3a mainly methylates the H19 and Dlk1/Gtl2 DMRs and a short interspersed repeat SineB1. Both Dnmt3a and Dnmt3b were involved in the methylation of Rasgrf1 DMR and long interspersed repeats IAP and Line1. Only Dnmt3b was required for the methylation of the satellite repeats. These results indicate both common and differential target specificities of Dnmt3a and Dnmt3b in vivo. Lastly, all these sequences showed moderate to severe hypomethylation in Dnmt3L-deficient prospermatogonia, indicating the critical function and broad specificity of this factor in de novo methylation.]]> Sun, 08 Jul 2007 21:00:00 PDT Fernández-Gonzalez R, Ramirez MA, Bilbao A, De Fonseca FR, Gutiérrez-Adán A
Mol Reprod Dev (Sep 2007)

The foetal origins of adult diseases or Barker hypothesis suggests that there can be adverse in uterus effects on the foetus that can lead to certain diseases in adults. Extending this hypothesis to the early stages of embryo development, in particular, to preimplantation stages, it was recently demonstrated that, long-term programming of postnatal development, growth and physiology can be irreversibly affected during this period of embryo development by suboptimal in vitro culture (IVC). As an example, it was found in two recent studies that, mice derived from embryos cultured in suboptimal conditions can suffer from obesity, increased anxiety, and deficiencies on their implicit memory system. In addition, it was observed that suboptimal IVC can cause disease in mature animals by promoting alterations in their genetic imprinting during preimplantation development. Imprinting and other epigenetic mechanisms control the establishment and maintenance of gene expression patterns in the embryo, placenta and foetus. The previously described observations, suggest that the loss of epigenetic regulation during preimplantation development may lead to severe long-term effects. Although mostly tested in rodents, the hypothesis that underlies these studies can also fit assisted reproductive technology (ART) procedures in other species, including humans. The lack of information on how epigenetic controls are lost during IVC, and on the long-term consequences of ART, underscore the necessity for sustained epigenetic analysis of embryos produced in vitro and long-term tracking of the health of the human beings conceived using these procedures. Mol. Reprod. Dev. 74: 1149-1156, 2007. (c) 2007 Wiley-Liss, Inc.]]> Mon, 02 Jul 2007 21:00:00 PDT Mikkelsen TS, Wakefield MJ, Aken B, Amemiya CT, Chang JL, Duke S, Garber M, Gentles AJ, Goodstadt L, Heger A, Jurka J, Kamal M, Mauceli E, Searle SM, Sharpe T, Baker ML, Batzer MA, Benos PV, Belov K, Clamp M, Cook A, Cuff J, Das R, Davidow L, Deakin JE, Fazzari MJ, Glass JL, Grabherr M, Greally JM, Gu W, Hore TA, Huttley GA, Kleber M, Jirtle RL, Koina E, Lee JT, Mahony S, Marra MA, Miller RD, Nicholls RD, Oda M, Papenfuss AT, Parra ZE, Pollock DD, Ray DA, Schein JE, Speed TP, Thompson K, VandeBerg JL, Wade CM, Walker JA, Waters PD, Webber C, Weidman JR, Xie X, Zody MC, Baldwin J, Abdouelleil A, Abdulkadir J, Abebe A, Abera B, Abreu J, Acer SC, Aftuck L, Alexander A, An P, Anderson E, Anderson S, Arachi H, Azer M, Bachantsang P, Barry A, Bayul T, Berlin A, Bessette D, Bloom T, Bloom T, Boguslavskiy L, Bonnet C, Boukhgalter B, Bourzgui I, Brown A, Cahill P, Channer S, Cheshatsang Y, Chuda L, Citroen M, Collymore A, Cooke P, Costello M, D'Aco K, Daza R, De Haan G, DeGray S, DeMaso C, Dhargay N, Dooley K, Dooley E, Doricent M, Dorje P, Dorjee K, Dupes A, Elong R, Falk J, Farina A, Faro S, Ferguson D, Fisher S, Foley CD, Franke A, Friedrich D, Gadbois L, Gearin G, Gearin CR, Giannoukos G, Goode T, Graham J, Grandbois E, Grewal S, Gyaltsen K, Hafez N, Hagos B, Hall J, Henson C, Hollinger A, Honan T, Huard MD, Hughes L, Hurhula B, Husby ME, Kamat A, Kanga B, Kashin S, Khazanovich D, Kisner P, Lance K, Lara M, Lee W, Lennon N, Letendre F, LeVine R, Lipovsky A, Liu X, Liu J, Liu S, Lokyitsang T, Lokyitsang Y, Lubonja R, Lui A, MacDonald P, Magnisalis V, Maru K, Matthews C, McCusker W, McDonough S, Mehta T, Meldrim J, Meneus L, Mihai O, Mihalev A, Mihova T, Mittelman R, Mlenga V, Montmayeur A, Mulrain L, Navidi A, Naylor J, Negash T, Nguyen T, Nguyen N, Nicol R, Norbu C, Norbu N, Novod N, O'Neill B, Osman S, Markiewicz E, Oyono OL, Patti C, Phunkhang P, Pierre F, Priest M, Raghuraman S, Rege F, Reyes R, Rise C, Rogov P, Ross K, Ryan E, Settipalli S, Shea T, Sherpa N, Shi L, Shih D, Sparrow T, Spaulding J, Stalker J, Stange-Thomann N, Stavropoulos S, Stone C, Strader C, Tesfaye S, Thomson T, Thoulutsang Y, Thoulutsang D, Topham K, Topping I, Tsamla T, Vassiliev H, Vo A, Wangchuk T, Wangdi T, Weiand M, Wilkinson J, Wilson A, Yadav S, Young G, Yu Q, Zembek L, Zhong D, Zimmer A, Zwirko Z, Jaffe DB, Alvarez P, Brockman W, Butler J, Chin C, Gnerre S, MacCallum I, Graves JA, Ponting CP, Breen M, Samollow PB, Lander ES, Lindblad-Toh K
Nature (May 2007)

We report a high-quality draft of the genome sequence of the grey, short-tailed opossum (Monodelphis domestica). As the first metatherian ('marsupial') species to be sequenced, the opossum provides a unique perspective on the organization and evolution of mammalian genomes. Distinctive features of the opossum chromosomes provide support for recent theories about genome evolution and function, including a strong influence of biased gene conversion on nucleotide sequence composition, and a relationship between chromosomal characteristics and X chromosome inactivation. Comparison of opossum and eutherian genomes also reveals a sharp difference in evolutionary innovation between protein-coding and non-coding functional elements. True innovation in protein-coding genes seems to be relatively rare, with lineage-specific differences being largely due to diversification and rapid turnover in gene families involved in environmental interactions. In contrast, about 20% of eutherian conserved non-coding elements (CNEs) are recent inventions that postdate the divergence of Eutheria and Metatheria. A substantial proportion of these eutherian-specific CNEs arose from sequence inserted by transposable elements, pointing to transposons as a major creative force in the evolution of mammalian gene regulation.]]> Sun, 13 May 2007 21:00:00 PDT Hunter P
EMBO Rep (May 2007)

]]> Mon, 30 Apr 2007 21:00:00 PDT Ooi SL, Henikoff S
Curr Opin Cell Biol (Apr 2007)

Germ cells have the same DNA sequence as somatic cells, but the processes that act on their chromatin are different. Germline chromatin undergoes a series of dramatic remodeling events during the life cycle of an organism. Different aspects of germline chromatin have been dissected in recent years, such as differences between the sex chromosomes and autosomes in histone variants and modifications. Excitingly, histone dynamics have recently been implicated in imprinted X inactivation and genomic imprinting processes that are independent of DNA methylation. Taken together with observations of core histone retention in mature sperm of diverse animals, histones have become prime candidates for mediating germline epigenetic inheritance.]]> Sun, 29 Apr 2007 21:00:00 PDT Suzuki S, Ono R, Narita T, Pask AJ, Shaw G, Wang C, Kohda T, Alsop AE, Marshall Graves JA, Kohara Y, Ishino F, Renfree MB, Kaneko-Ishino T
PLoS Genet (Apr 2007)

Among mammals, only eutherians and marsupials are viviparous and have genomic imprinting that leads to parent-of-origin-specific differential gene expression. We used comparative analysis to investigate the origin of genomic imprinting in mammals. PEG10 (paternally expressed 10) is a retrotransposon-derived imprinted gene that has an essential role for the formation of the placenta of the mouse. Here, we show that an orthologue of PEG10 exists in another therian mammal, the marsupial tammar wallaby (Macropus eugenii), but not in a prototherian mammal, the egg-laying platypus (Ornithorhynchus anatinus), suggesting its close relationship to the origin of placentation in therian mammals. We have discovered a hitherto missing link of the imprinting mechanism between eutherians and marsupials because tammar PEG10 is the first example of a differentially methylated region (DMR) associated with genomic imprinting in marsupials. Surprisingly, the marsupial DMR was strictly limited to the 5' region of PEG10, unlike the eutherian DMR, which covers the promoter regions of both PEG10 and the adjacent imprinted gene SGCE. These results not only demonstrate a common origin of the DMR-associated imprinting mechanism in therian mammals but provide the first demonstration that DMR-associated genomic imprinting in eutherians can originate from the repression of exogenous DNA sequences and/or retrotransposons by DNA methylation.]]> Sun, 15 Apr 2007 21:00:00 PDT Lalande M, Calciano MA
Cell Mol Life Sci (Apr 2007)

Angelman syndrome (AS) is a neurogenetic disorder characterized by severe mental retardation, ataxia, seizures, EEG abnormalities and bouts of inappropriate laughter. AS individuals fail to inherit a normal active maternal copy of ubiquitin protein ligase E3A (UBE3A). UBE3A is subject to genomic imprinting, with predominant transcription of the maternal allele in brain. The known genetic causes of AS are maternal deletion of chromosome 15q11-q13, paternal chromosome 15 uniparental disomy, UBE3A mutation and an abnormality of the imprinting process, termed imprinting defect. There remain major questions concerning the molecular pathogenesis of AS, including: 1) the mechanisms underlying the imprinting defect class of AS, 2) the identity of proteins targeted by UBE3A, 3) the role of a noncoding antisense transcript in regulating UBE3A imprinting and 4) the contribution of other genes such as methyl-binding CpG-binding protein 2 and gamma-aminobutyric acid A receptor, subunit beta3 to the AS phenotype.]]> Wed, 11 Apr 2007 21:00:00 PDT Swaney WT, Curley JP, Champagne FA, Keverne EB
Proc Natl Acad Sci U S A (Mar 2007)

Mammalian imprinted genes are generally thought to have evolved as a result of conflict between parents; however, recent knockout studies suggest that coadaptation between mother and offspring may have been a significant factor. We present evidence that the same imprinted gene that regulates mammalian maternal care and offspring development also regulates male sexual behavior and olfaction. We have shown that the behavior of male mice carrying a knockout of the imprinted gene Peg3 does not change with sexual experience and that the mice are consequently unable to improve their copulatory abilities or olfactory interest in female odor cues after mating experience. Forebrain activation, as indexed by female odor-induced c-Fos protein induction, fails to increase with sexual experience, providing a neural basis for the behavioral deficits that the male mice display. The behavioral and neural effects of the Peg3 knockout show that this imprinted gene has evolved to regulate multiple and varied aspects of reproduction, from male sexual behavior to female maternal care, and the development of offspring. Moreover, sexual experience-driven behavioral changes may represent an adaptive response that enables males to increase their reproductive potential over their lifespan, and the effects we have found suggest that the evolution of genomic imprinting has been influenced by coadaptation between males and females as well as between females and offspring.]]> Tue, 27 Mar 2007 21:00:00 PDT Jirtle RL, Weidman JR
Am Sci (Mar 2007)

]]> Fri, 16 Mar 2007 17:53:57 PDT Jirtle RL, Skinner MK
Nat Rev Genet (Apr 2007)

Epidemiological evidence increasingly suggests that environmental exposures early in development have a role in susceptibility to disease in later life. In addition, some of these environmental effects seem to be passed on through subsequent generations. Epigenetic modifications provide a plausible link between the environment and alterations in gene expression that might lead to disease phenotypes. An increasing body of evidence from animal studies supports the role of environmental epigenetics in disease susceptibility. Furthermore, recent studies have demonstrated for the first time that heritable environmentally induced epigenetic modifications underlie reversible transgenerational alterations in phenotype. Methods are now becoming available to investigate the relevance of these phenomena to human disease.]]> Thu, 15 Mar 2007 21:00:00 PDT Gomes MV, Gomes CC, Pinto W, Ramos ES
Am J Med Genet A (Mar 2007)

]]> Tue, 27 Feb 2007 21:00:00 PST Feil R, Berger F
Trends Genet (Feb 2007)

Parental genomic imprinting is characterized by the expression of a selected panel of genes from one of the two parental alleles. Recent evidence shows that DNA methylation and histone modifications are responsible for this parent-of-origin-dependent expression of imprinted genes. Because similar epigenetic marks have been recruited independently in plants and mammals, the only organisms in which imprinted gene loci have been identified so far, this phenomenon represents a case for convergent evolution. Here we discuss the emerging parallels in imprinting in both taxa. We also describe the significance of imprinting for reproduction and discuss potential models for its evolution.]]> Thu, 22 Feb 2007 21:00:00 PST Bobetsis YA, Barros SP, Lin DM, Weidman JR, Dolinoy DC, Jirtle RL, Boggess KA, Beck JD, Offenbacher S
J Dent Res (Feb 2007)

Maternal oral infection, caused by bacteria such as C. rectus or P. gingivalis, has been implicated as a potential source of placental and fetal infection and inflammatory challenge, which increases the relative risk for pre-term delivery and growth restriction. Intra-uterine growth restriction has also been reported in various animal models infected with oral organisms. Analyzing placental tissues of infected growth-restricted mice, we found down-regulation of the imprinted Igf2 gene. Epigenetic modification of imprinted genes via changes in DNA methylation plays a critical role in fetal growth and development programming. Here, we assessed whether C. rectus infection mediates changes in the murine placenta Igf2 methylation patterns. We found that infection induced hypermethylation in the promoter region-P0 of the Igf2 gene. This novel finding, correlating infection with epigenetic alterations, provides a mechanism linking environmental signals to placental phenotype, with consequences for development.]]> Wed, 24 Jan 2007 21:00:00 PST Do Kim J, Hinz AK, Ha Choo J, Stubbs L, Kim J
Genomics (Feb 2007)

Imprinting control regions (ICRs) often harbor tandem arrays of transcription factor binding sites, as demonstrated by the identification of multiple YY1 binding sites within the ICRs of Peg3, Nespas, and Xist/Tsix domains. In the current study, we have sought to characterize possible roles for YY1 in transcriptional control and epigenetic modification of these imprinted domains. RNA interference-based knockdown experiments in Neuro2A cells resulted in overall transcriptional up-regulation of most of the imprinted genes within the Peg3 domain and also, concomitantly, caused significant loss in the DNA methylation of the Peg3 differentially methylated region. A similar overall and coordinated expression change was also observed for the imprinted genes of the Gnas domain: up-regulation of Nespas and down-regulation of Nesp and Gnasxl. YY1 knockdown also resulted in changes in the expression levels of Xist and Snrpn. These results support the idea that YY1 plays a major role, as a trans factor, in the control of these imprinted domains.]]> Thu, 11 Jan 2007 21:00:00 PST Long JE, Cai X
Gene (Feb 2007)

Epigenetic reprogramming has a crucial role in establishing nuclear totipotency in normal development and in cloned animals. Insulin-like growth factor-2 receptor (Igf-2r) is a tissue-specifically and species-dependently imprinted gene, regulated by epigenetic modifications. The diversity of Igf-2r imprinting suggests that the success of animal cloning may be species-dependent. To determine the relation between epigenetic modifications and Igf-2r expression in cattle, and explore whether this gene was correctly imprinted and reprogrammed after nuclear transfer, we quantified Igf-2r mRNA in a cattle cell line after treated with an inhibitor of DNA methylation transferase or an inhibitor of histone deacetylase, and confirmed that DNA methylation and histone acetylation could regulate this gene expression. CpG island searching showed that there is a conservative imprinting control region (ICR) within the second intron of Igf-2r in cattle, analogous to mice and sheep, regulating this gene imprinting. DNA methylation analysis in sperm and blood cells showed that DNA methylation at Igf-2r ICR2 was reprogrammed in normal cattle. The methylation at Igf-2r ICR2 showed significant variation in tissues, such as blood, liver, brain, heart and heart. It suggested that Igf-2r imprinting was tissue-specifically regulated. In cloned cattle, DNA methylation at Igf-2r ICR2 was markedly altered in comparison with normal fetus, while patterns of DNA methylation at Igf-2r 3'-UTR (3-terminal untranslated region) were similar to normal fetus, it indicated that 3'-UTR was not significantly altered by cloning procedures, but DNA methylation at the locus of gene imprinting was disrupted and not completely reprogrammed after nuclear transfer.]]> Mon, 01 Jan 2007 21:00:00 PST Rossignol S, Steunou V, Chalas C, Kerjean A, Rigolet M, Viegas-Pequignot E, Jouannet P, Le Bouc Y, Gicquel C
J Med Genet (Dec 2006)

BACKGROUND: Genomic imprinting refers to an epigenetic marking resulting in monoallelic gene expression and has a critical role in fetal development. Various imprinting diseases have recently been reported in humans and animals born after the use of assisted reproductive technology (ART). All the epimutations implicated involve a loss of methylation of the maternal allele (demethylation of KvDMR1/KCNQ1OT1 in Beckwith-Wiedemann syndrome (BWS), demethylation of SNRPN in Angelman syndrome and demethylation of DMR2/IGF2R in large offspring syndrome), suggesting that ART impairs the acquisition or maintenance of methylation marks on maternal imprinted genes. However, it is unknown whether this epigenetic imprinting error is random or restricted to a specific imprinted domain. AIM: To analyse the methylation status of various imprinted genes (IGF2R gene at 6q26, PEG1/MEST at 7q32, KCNQ1OT1 and H19 at 11p15.5, and SNRPN at 15q11-13) in 40 patients with BWS showing a loss of methylation at KCNQ1OT1 (11 patients with BWS born after the use of ART and 29 patients with BWS conceived naturally). RESULTS: 3 of the 11 (27%) patients conceived using ART and 7 of the 29 (24%) patients conceived normally displayed an abnormal methylation at a locus other than KCNQ1OT1. CONCLUSIONS: Some patients with BWS show abnormal methylation at loci other than the 11p15 region, and the involvement of other loci is not restricted to patients with BWS born after ART was used. Moreover, the mosaic distribution of epimutations suggests that imprinting is lost after fertilisation owing to a failure to maintain methylation marks during pre-implantation development.]]> Sun, 03 Dec 2006 21:00:00 PST Cropley JE, Suter CM, Beckman KB, Martin DI
Proc Natl Acad Sci U S A (Nov 2006)

Environmental effects on phenotype can be mediated by epigenetic modifications. The epigenetic state of the murine A(vy) allele is highly variable, and determines phenotypic effects that vary in a mosaic spectrum that can be shifted by in utero exposure to methyl donor supplementation. We have asked if methyl donor supplementation affects the germ-line epigenetic state of the A(vy) allele. We find that the somatic epigenetic state of A(vy) is affected by in utero methyl donor supplementation only when the allele is paternally contributed. Exposure to methyl donor supplementation during midgestation shifts A(vy) phenotypes not only in the mice exposed as fetuses, but in their offspring. This finding indicates that methyl donors can change the epigenetic state of the A(vy) allele in the germ line, and that the altered state is retained through the epigenetic resetting that takes place in gametogenesis and embryogenesis. Thus a mother's diet may have an enduring influence on succeeding generations, independent of later changes in diet. Although other reports have suggested such heritable epigenetic changes, this study demonstrates that a specific mammalian gene can be subjected to germ-line epigenetic change.]]> Sat, 18 Nov 2006 21:00:00 PST Ethan Watters
Discover (Nov 2006)

]]> Tue, 31 Oct 2006 14:48:32 PST Dolinoy DC, Weidman JR, Jirtle RL
Reprod Toxicol (Apr 2007)

Traditional studies on the combined effects of genetics and the environment on individual variation in disease susceptibility primarily focus on single nucleotide polymorphisms that influence toxicant uptake and metabolism. A growing body of evidence, however, suggests that epigenetic mechanisms of gene regulation, such as DNA methylation and chromatin modification, are also influenced by the environment, and play an important role in the fetal basis of adult disease susceptibility. Studying the influence of early environmental exposures on metastable epialleles and imprinted genes offers insight into the mechanisms affecting the fetal epigenome and subsequent adult disease susceptibility. In this review, we introduce the reader to the field of environmental epigenomics, provide information on the important epigenetic control mechanisms and epigenetic phenomena in mammals, and summarize the current body of literature on nutritional and environmental influences affecting the epigenome.]]> Tue, 17 Oct 2006 21:00:00 PDT Michels KB, Xue F
Int J Cancer (Nov 2006)

Breast cancer may originate in utero. We reviewed the available evidence on the association between birthweight and the risk of breast cancer. To date, 26 research papers addressing this issue have been published. The majority of studies identified a positive link between birthweight and premenopausal, but not postmenopausal, breast cancer. The relative risk estimate for breast cancer comparing women with high birthweight to women with low birthweight combining all studies including both pre- and postmenopausal breast cancer was 1.23 (95% confidence interval 1.13-1.34). The mechanisms underlying this association likely include elevated levels of growth factors that may increase the number of susceptible stem cells in the mammary gland or initiate tumors through DNA mutations. Loss of imprinting (LOI) of growth hormone genes relevant for intrauterine growth, such as insulin-like growth factor 2 (IGF2), leads to abnormally high levels of these hormones evidenced by high birthweight. LOI of IGF2 has also been found in mammary tumor tissue. The role of environmental factors that stimulate such epigenetic regulation of gene expression remains to be elucidated. (c) 2006 Wiley-Liss, Inc.]]> Tue, 05 Sep 2006 21:00:00 PDT Weidman JR, Dolinoy DC, Maloney KA, Cheng JF, Jirtle RL
Epigenetics (Jan 2006)

Phylogenetic comparison of extant mammals with divergent imprint status is a powerful method for identifying critical components of imprint regulation at individual loci. The entire genomic region of Igf2r in the imprinted marsupials, Didelphis virginiana and Monodelphis domestica, and the non-imprinted monotreme, Ornithorhynchus anatinus, was isolated and sequenced. Genetic and epigenetic comparisons of over 160 kb of sequence were then performed in five distinct mammalian species. Surprisingly, opossum Igf2r is imprinted and maternally expressed despite the absence of the intron 2 CpG island (CpG2), antisense Igf2r RNA (Air) and differential methylation of the promoter (CpG1) required for imprinting of this gene in mice. These findings demonstrate that the genomic elements necessary for imprinted Igf2r expression in eutherians are not required for imprinting of this locus in metatherians. Thus, the regulatory mechanisms of Igf2r imprinting did not evolve convergently within the Therian subclass of mammals.]]> Mon, 24 Jul 2006 05:47:08 PDT Maffini MV, Rubin BS, Sonnenschein C, Soto AM
Mol Cell Endocrinol (Jul 2006)

Epidemiological studies have reported that during the last 60 years the quantity and quality of human sperm has decreased and the incidence of male genital tract defects, testicular, prostate and breast cancer has increased. During the same time period, developmental, reproductive and endocrine effects have also been documented in wildlife species. The last six decades have witnessed a massive introduction of hormonally active synthetic chemicals into the environment leading some to postulate that the diverse outcomes documented in human and wildlife populations might be the result of extemporaneous exposure to xenoestrogens during development. The estrogen-mimic bisphenol-A (BPA) is used as a model agent for endocrine disruption. BPA is used in the manufacture of polycarbonate plastics and epoxy resins from which food and beverage containers and dental materials are made. Perinatal exposure to environmentally relevant BPA doses results in morphological and functional alterations of the male and female genital tract and mammary glands that may predispose the tissue to earlier onset of disease, reduced fertility and mammary and prostate cancer.]]> Mon, 17 Jul 2006 21:00:00 PDT Badcock C, Crespi B
J Evol Biol (Jul 2006)

We describe a new hypothesis for the development of autism, that it is driven by imbalances in brain development involving enhanced effects of paternally expressed imprinted genes, deficits of effects from maternally expressed genes, or both. This hypothesis is supported by: (1) the strong genomic-imprinting component to the genetic and developmental mechanisms of autism, Angelman syndrome, Rett syndrome and Turner syndrome; (2) the core behavioural features of autism, such as self-focused behaviour, altered social interactions and language, and enhanced spatial and mechanistic cognition and abilities, and (3) the degree to which relevant brain functions and structures are altered in autism and related disorders. The imprinted brain theory of autism has important implications for understanding the genetic, epigenetic, neurological and cognitive bases of autism, as ultimately due to imbalances in the outcomes of intragenomic conflict between effects of maternally vs. paternally expressed genes.]]> Sun, 18 Jun 2006 21:00:00 PDT Dolinoy DC, Weidman JR, Waterland RA, Jirtle RL
Environ Health Perspect (Apr 2006)

Genistein, the major phytoestrogen in soy, is linked to diminished female reproductive performance and to cancer chemoprevention and decreased adipose deposition. Dietary genistein may also play a role in the decreased incidence of cancer in Asians compared with Westerners, as well as increased cancer incidence in Asians immigrating to the United States. Here, we report that maternal dietary genistein supplementation of mice during gestation, at levels comparable with humans consuming high-soy diets, shifted the coat color of heterozygous viable yellow agouti (A(vy/a) offspring toward pseudoagouti. This marked phenotypic change was significantly associated with increased methylation of six cytosine-guanine sites in a retrotransposon upstream of the transcription start site of the Agouti gene. The extent of this DNA methylation was similar in endodermal, mesodermal, and ectodermal tissues, indicating that genistein acts during early embryonic development. Moreover, this genistein-induced hypermethylation persisted into adulthood, decreasing ectopic Agouti expression and protecting offspring from obesity. Thus, we provide the first evidence that in utero dietary genistein affects gene expression and alters susceptibility to obesity in adulthood by permanently altering the epigenome.]]> Sun, 02 Apr 2006 21:00:00 PDT Vu TH, Jirtle RL, Hoffman AR
Cytogenet Genome Res (Jan 2006)

The epigenetic marks on the IGF2R gene that encodes a receptor responsible for IGF-II degradation consist of differentially methylated DNA in association with multiple modifications on the associated histones. We review these epigenetic marks across various species during the evolution of IGF2R imprinting. Both IGF2 and IGF2R genesare imprinted in the mammal lineage that diverged from Monotremata approximately 150 million years ago. While IGF2 is consistently imprinted in all mammals following its divergence, IGF2R imprinting disappears in the Euarchonta lineage, including human species, approximately 75 million years ago. Differential DNA methylation marks on the two parental alleles correlate with imprinting in all imprinted genes including IGF2R. While the DNA methylation marks in the IGF2R promoter region 1 (DMR1) correlate with IGF2R allelic expression, the DNA methylation marks in the intron region 2 (DMR2) fail to correlate with IGF2R imprinting status in a number of species. Human IGF2R and mouse neuronal Igf2r are not imprinted despite the presence of DMR2. We have noted that human IGF2R is not imprinted in more than 100 informative samples including various tumor tissues. Furthermore, opossum (Marsupialia) IGF2R is consistently imprinted despite the absence of DMR2. These lines of evidence indicate that DNA methylation marks in DMR2 are neither necessary nor sufficient for consistent imprinting of IGF2R across species. Histone modification marks, however, correlate more consistently with the tissue-specific and species-specific imprinting status of IGF2R in human and mouse. Acetylated histone H3 and H4 and methylated lysine 4 of H3 (H3-K4Me) associate with transcriptionally active alleles while tri-methylated lysine 9 of H3 (H3-K9Me3) marks the silenced alleles. In the mouse, an antisense non-coding transcript called Air is transcribed from DMR2 on the paternal allele, and this imprinted transcript plays a central role in Igf2r imprinting. Mouse Igf2r imprinting depends on an Air RNA while the existence of AIR in other species is unknown. Overall, DNA methylation, histone acetylation, and histone methylation play a vital role in coordinating IGF2R allelic expression across all species. Rare monoallelic or skewed allelic expression of human IGF2R and their biological importance warrants further rigorous study.]]> Thu, 30 Mar 2006 21:00:00 PST Weidman JR, Maloney KA, Jirtle RL
Mamm Genome (Feb 2006)

Imprinted genes are monoallelically expressed in a parent-of-origin manner and were previously identified in both marsupials and eutherians, but not in monotremes. Phylogenetic comparison of imprinted domains is a powerful tool for investigating the molecular and adaptive evolution of this unique gene regulatory mechanism. Herein, we report that multiple transcripts of Dlk1 (Delta, Drosophila, Homolog-like 1) are expressed in the opossum, but none are imprinted. Thus, we provide the first example of a reciprocally imprinted gene domain in which imprinting evolved in a common ancestor to eutherian rather than therian mammals. Moreover, the reciprocally imprinted Meg3 (Maternally Expressed Gene 3), found downstream of Dlk1 in eutherian mammals, is absent in the opossum. We propose that the Meg3 sequence integrated into the eutherian Dlk1 domain via a LINE-1 element and that Dlk1 became imprinted in eutherian mammals only after this downstream integration. These findings clearly demonstrate that imprinted genes did not all evolve before the divergence of marsupials and eutherians.]]> Tue, 07 Feb 2006 21:00:00 PST Morison IM, Ramsay JP, Spencer HG
Trends Genet (Aug 2005)

Genomic imprinting, the parent-of-origin-specific silencing of a small proportion of genes, introduces a paradoxical vulnerability of hemizygosity into the diploid mammalian genome. To facilitate the evaluation of the biological and evolutionary significance of imprinting, we have collated a census of known imprinted genes, listing 83 transcriptional units of which 29 are imprinted in both humans and mice. There is a high level of discordance of imprinting status between the mouse and human, even when cases in which the orthologue is absent from one species are excluded. A high proportion of imprinted genes are noncoding RNAs or genes derived by retrotransposition. Accumulation of functional and comparative data for these genes will improve our understanding of imprinting and its contribution to mammalian evolution.]]> Mon, 18 Jul 2005 21:00:00 PDT Evans HK, Weidman JR, Cowley DO, Jirtle RL
Mol Biol Evol (Aug 2005)

Imprinted genes are parent-of-origin dependent, monoallelically expressed genes present in marsupials and eutherian mammals. Altered expression of imprinted genes plays a significant role in the etiology of a variety of human disorders and diseases. Nevertheless, the regulatory mechanisms of imprinting remain poorly defined. The imprinted gene Neuronatin (Nnat) is an excellent candidate for studying imprinting because it resides within the 8.5-kb intron of the nonimprinted gene Bladder Cancer-Associated Protein (Blcap) and is the only imprinted gene within the region. A phylogenetic comparison of this micro-imprinted domain in human, mouse, and rat revealed several candidates for imprint control, including tandem repeats and putative binding sites for trans- acting factors known to be involved in chromatin remodeling. Genome-wide phylogenetic comparisons of species from the three major extant mammalian clades failed, however, to show any evidence of Nnat outside the eutherian lineage. Thus, Nnat is the first identified eutherian-specific imprinted gene, demonstrating that imprinted genes did not arise at a single point during evolution. This finding also suggests that the complexity of imprinting regulation observed at other loci may, in part, be directly related to the amount of time they have been imprinted.]]> Sun, 10 Jul 2005 21:00:00 PDT Luedi PP, Hartemink AJ, Jirtle RL
Genome Res (Jun 2005)

Imprinted genes are epigenetically modified genes whose expression is determined according to their parent of origin. They are involved in embryonic development, and imprinting dysregulation is linked to cancer, obesity, diabetes, and behavioral disorders such as autism and bipolar disease. Herein, we train a statistical model based on DNA sequence characteristics that not only identifies potentially imprinted genes, but also predicts the parental allele from which they are expressed. Of 23,788 annotated autosomal mouse genes, our model identifies 600 (2.5%) to be potentially imprinted, 64% of which are predicted to exhibit maternal expression. These predictions allowed for the identification of putative candidate genes for complex conditions where parent-of-origin effects are involved, including Alzheimer disease, autism, bipolar disorder, diabetes, male sexual orientation, obesity, and schizophrenia. We observe that the number, type, and relative orientation of repeated elements flanking a gene are particularly important in predicting whether a gene is imprinted.]]> Wed, 01 Jun 2005 21:00:00 PDT Davies W, Isles A, Smith R, Karunadasa D, Burrmann D, Humby T, Ojarikre O, Biggin C, Skuse D, Burgoyne P, Wilkinson L
Nat Genet (Jun 2005)

Imprinted genes show differential expression between maternal and paternal alleles as a consequence of epigenetic modification that can result in 'parent-of-origin' effects on phenotypic traits. There is increasing evidence from mouse and human studies that imprinted genes may influence behavior and cognitive functioning. Previous work in girls with Turner syndrome (45,XO) has suggested that there are X-linked parent-of-origin effects on brain development and cognitive functioning, although the interpretation of these data in terms of imprinted gene effects has been questioned. We used a 39,XO mouse model to examine the influence of the parental origin of the X chromosome on cognitive behaviors and expression of X-linked genes in brain. Our findings confirm the existence of X-linked imprinted effects on cognitive processes and identify a new maternally expressed imprinted gene candidate on the X chromosome, Xlr3b, which may be of importance in mediating the behavioral effects.]]> Thu, 26 May 2005 21:00:00 PDT Raefski AS, O'Neill MJ
Nat Genet (Jun 2005)

Complete or partial monosomy with respect to the X chromosome is the genetic basis of Turner syndrome in human females. Individuals with Turner syndrome have a spectrum of anatomical, physiological and behavioral phenotypes with expressivity dependent on the extent of monosomy and the parental origin of the single X. Parent-of-origin influences on social cognition in Turner syndrome might be due to the presence of imprinted genes on the X. Imprinting of X-linked genes has also been implicated in the male prevalence of autistic spectrum disorders, in male sexual orientation and in the developmental delay of XO mouse embryos. The only molecular evidence for X-chromosome imprinting, however, concerns X-chromosome inactivation in specific circumstances and does not account for these phenotypes. Using a mouse model for Turner syndrome, we searched for locus-specific imprinting of X-linked genes in developing brain. We identified a cluster of X-linked genes containing at least three genes that show transcriptional repression of paternal alleles. Imprinting of these three genes, Xlr3b, Xlr4b and Xlr4c, is independent of X-chromosome inactivation and has a dynamic and complex pattern of tissue and stage specificity.]]> Thu, 26 May 2005 21:00:00 PDT Barker DJ
J Am Coll Nutr (Dec 2004)

Low birthweight is now known to be associated with increased rates of coronary heart disease and the related disorders stroke, hypertension and non-insulin dependent diabetes. These associations have been extensively replicated in studies in different countries and are not the result of confounding variables. They extend across the normal range of birthweight and depend on lower birthweights in relation to the duration of gestation rather than the effects of premature birth. The associations are thought to be consequences of developmental plasticity, the phenomenon by which one genotype can give rise to a range of different physiological or morphological states in response to different environmental conditions during development. Recent observations have shown that impaired growth in infancy and rapid childhood weight gain exacerbate the effects of impaired prenatal growth. A new vision of optimal early human development is emerging which takes account of both short and long-term outcomes.]]> Sun, 09 Jan 2005 21:00:00 PST Plagge A, Gordon E, Dean W, Boiani R, Cinti S, Peters J, Kelsey G
Nat Genet (Aug 2004)

Genomic imprinting, by which maternal and paternal alleles of some genes have different levels of activity, has profound effects on growth and development of the mammalian fetus. The action of imprinted genes after birth, in particular while the infant is dependent on maternal provision of nutrients, is far less well understood. We disrupted a paternally expressed transcript at the Gnas locus, Gnasxl, which encodes the unusual Gs alpha isoform XL alpha s. Mice with mutations in Gnasxl have poor postnatal growth and survival and a spectrum of phenotypic effects that indicate that XL alpha s controls a number of key postnatal physiological adaptations, including suckling, blood glucose and energy homeostasis. Increased cAMP levels in brown adipose tissue of Gnasxl mutants and phenotypic comparison with Gnas mutants suggest that XL alpha s can antagonize Gs alpha-dependent signaling pathways. The opposing effects of maternally and paternally expressed products of the Gnas locus provide tangible molecular support for the parental-conflict hypothesis of imprinting.]]> Thu, 29 Jul 2004 21:00:00 PDT Williamson CM, Ball ST, Nottingham WT, Skinner JA, Plagge A, Turner MD, Powles N, Hough T, Papworth D, Fraser WD, Maconochie M, Peters J
Nat Genet (Aug 2004)

Genomic imprinting brings about allele-specific silencing according to parental origin. Silencing is controlled by cis-acting regulatory regions that are differentially marked during gametogenesis and can act over hundreds of kilobases to silence many genes. Two candidate imprinting control regions (ICRs) have been identified at the compact imprinted Gnas cluster on distal mouse chromosome 2, one at exon 1A upstream of Gnas itself and one covering the promoters for Gnasxl and the antisense Nespas (ref. 8). This imprinted cluster is complex, containing biallelic, maternally and paternally expressed transcripts that share exons. Gnas itself is mainly biallelically expressed but is weakly paternally repressed in specific tissues. Here we show that a paternally derived targeted deletion of the germline differentially methylated region at exon 1A abolishes tissue-specific imprinting of Gnas. This rescues the abnormal phenotype of mice with a maternally derived Gnas mutation. Imprinting of alternative transcripts, Nesp, Gnasxl and Nespas (ref. 13), in the cluster is unaffected. The results establish that the differentially methylated region at exon 1A contains an imprinting control element that specifically regulates Gnas and comprises a characterized ICR for a gene that is only weakly imprinted in a minority of tissues. There must be a second ICR regulating the alternative transcripts.]]> Thu, 29 Jul 2004 21:00:00 PDT Della Vedova CB, Cone KC
Plant Cell (Jun 2004)

Paramutation has been studied extensively in maize since R.A. Brink described a heritable alteration of the r locus that defied principles of Mendelian inheritance (Brink, 1956). A recent publication on paramutation in maize now provides convincing evidence that chromatin-level regulation underlies the phenotypic differences between alleles that participate in paramutation (Stam et al., 2002a). Two additional articles—one detailing paramutation-like effects associated with mammalian imprinting and the other describing paramutation after a change in ploidy in Arabidopsis—challenge us to understand how these cases fit into the developing paradigm explaining the molecular basis for paramutation (Herman et al., 2003; Mittelsten Scheid et al., 2003). Together, these studies suggest a mechanistic link between paramutation and other types of chromatin-level epigenetic regulation of gene expression.]]> Thu, 03 Jun 2004 21:00:00 PDT Schieve LA, Rasmussen SA, Buck GM, Schendel DE, Reynolds MA, Wright VC
Obstet Gynecol (Jun 2004)

As assisted reproductive technologies (ARTs) are increasingly used to overcome infertility, there is concern about the health of the children conceived. The empirical evidence for associations with outcomes related to child health is variable and should be evaluated with consideration of methodological shortcomings. Currently, there is convincing evidence that ART treatment may increase the risk of a few outcomes. Experimental laboratory studies document that various constituents in culture media affect various embryo characteristics both positively and negatively. Multiple-gestation pregnancy and birth are increased with ART, both because of multiple embryo transfer and embryo splitting. There is evidence of an increase in chromosomal abnormalities among pregnancies conceived using intracytoplasmic sperm injection and low birth weight and preterm delivery among singletons conceived with all types of ART; however, there remains uncertainty about whether these risks stem from the treatment or the parental infertility. For some outcomes, data of an increased risk with ART are suggestive at best largely because of lack of purposeful study of sufficient size and scope. These include specific perinatal morbidities, birth defects, developmental disabilities, and retinoblastoma. The evidence for an association between ART and spontaneous abortion is inconsistent and weak. There is inconclusive evidence that ART may be associated with genetic imprinting disorders. For childhood cancer, chronic conditions, learning and behavioral disorders, and reproductive effects there is insufficient empirical research to date, but given the data for more proximal outcomes, these outcomes merit further study. Future research needs to address the unique methodological challenges underlying study in this area.]]> Tue, 01 Jun 2004 21:00:00 PDT Niemitz EL, Feinberg AP
Am J Hum Genet (Apr 2004)

A surprising set of recent observations suggests a link between assisted reproductive technology (ART) and epigenetic errors--that is, errors involving information other than DNA sequence that is heritable during cell division. An apparent association with ART was found in registries of children with Beckwith-Wiedemann syndrome, Angelman syndrome, and retinoblastoma. Here, we review the epidemiology and molecular biology behind these studies and those of relevant model systems, and we highlight the need for investigation of two major questions: (1) large-scale case-control studies of ART outcomes, including long-term assessment of the incidence of birth defects and cancer, and (2) investigation of the relationship between epigenetic errors in both offspring and parents, the specific methods of ART used, and the underlying infertility diagnoses. In addition, the components of proprietary commercial media used in ART procedures must be fully and publicly disclosed, so that factors such as methionine content can be assessed, given the relationship in animal studies between methionine exposure and epigenetic changes.]]> Mon, 15 Mar 2004 21:00:00 PST Feinberg AP, Tycko B
Nat Rev Cancer (Feb 2004)

Since its discovery in 1983, the epigenetics of human cancer has been in the shadows of human cancer genetics. But this area has become increasingly visible with a growing understanding of specific epigenetic mechanisms and their role in cancer, including hypomethylation, hypermethylation, loss of imprinting and chromatin modification. This timeline traces the field from its conception to the present day. It also addresses the genetic basis of epigenetic changes — an emerging area that promises to unite cancer genetics and epigenetics, and might serve as a model for understanding the epigenetic basis of human disease more generally.]]> Mon, 19 Jan 2004 21:00:00 PST Waterland RA, Jirtle RL
Mol Cell Biol (Aug 2003)

Early nutrition affects adult metabolism in humans and other mammals, potentially via persistent alterations in DNA methylation. With viable yellow agouti (A(vy)) mice, which harbor a transposable element in the agouti gene, we tested the hypothesis that the metastable methylation status of specific transposable element insertion sites renders them epigenetically labile to early methyl donor nutrition. Our results show that dietary methyl supplementation of a/a dams with extra folic acid, vitamin B(12), choline, and betaine alter the phenotype of their A(vy)/a offspring via increased CpG methylation at the A(vy) locus and that the epigenetic metastability which confers this lability is due to the A(vy) transposable element. These findings suggest that dietary supplementation, long presumed to be purely beneficial, may have unintended deleterious influences on the establishment of epigenetic gene regulation in humans.]]> Mon, 14 Jul 2003 21:00:00 PDT Murphy SK, Jirtle RL
Bioessays (Jun 2003)

In contrast to the biallelic expression of most genes, expression of genes subject to genomic imprinting is monoallelic and based on the sex of the transmitting parent. Possession of only a single active allele can lead to deleterious health consequences in humans. Aberrant expression of imprinted genes, through either genetic or epigenetic alterations, can result in developmental failures, neurodevelopmental and neurobehavioral disorders and cancer. The evolutionary emergence of imprinting occurred in a common ancestor to viviparous mammals after divergence from the egg-laying monotremes. Current evidence indicates that imprinting regulation in metatherian mammals differs from that in eutherian mammals. This suggests that imprinting mechanisms are evolving from those that were established 150 million years ago. Therefore, comparing genomic sequence of imprinted domains from marsupials and eutherians with those of orthologous regions in monotremes offers a potentially powerful bioinformatics approach for identifying novel imprinted genes and their regulatory elements. Such comparative studies will also further our understanding of the molecular evolution and phylogenetic distribution of imprinted genes.]]> Sun, 25 May 2003 21:00:00 PDT