'; ?> geneimprint : Hot off the Press http://www.geneimprint.com/site/hot-off-the-press Daily listing of the most recent articles in epigenetics and imprinting, collected from the PubMed database. en-us Thu, 26 Nov 2015 16:47:48 PST Thu, 26 Nov 2015 16:47:48 PST jirtle@radonc.duke.edu james001@jirtle.com Epigenetic mechanisms underlying arsenic-associated lung carcinogenesis. van Breda SG, Claessen SM, Lo K, van Herwijnen M, Brauers KJ, Lisanti S, Theunissen DH, Jennen DG, Gaj S, de Kok TM, Kleinjans JC
Arch Toxicol (Nov 2015)

Arsenic is an established human carcinogen, but the mechanisms through which it contributes to for instance lung cancer development are still unclear. As arsenic is methylated during its metabolism, it may interfere with the DNA methylation process, and is therefore considered to be an epigenetic carcinogen. In the present study, we hypothesize that arsenic is able to induce DNA methylation changes, which lead to changes in specific gene expression, in pathways associated with lung cancer promotion and progression. A549 human adenocarcinoma lung cells were exposed to a low (0.08 µM), intermediate (0.4 µM) and high (2 µM) concentration of sodium arsenite for 1, 2 and 8 weeks. DNA was isolated for whole-genome DNA methylation analyses using NimbleGen 2.1 M deluxe promoter arrays. In addition, RNA was isolated for whole-genome transcriptomic analysis using Affymetrix microarrays. Arsenic modulated DNA methylation and expression levels of hundreds of genes in a dose-dependent and time-dependent manner. By combining whole-genome DNA methylation and gene expression data with possibly involved transcription factors, a large molecular interaction network was created based on transcription factor-target gene pairs, consisting of 216 genes. A tumor protein p53 (TP53) subnetwork was identified, showing the interactions of TP53 with other genes affected by arsenic. Furthermore, multiple other new genes were discovered showing altered DNA methylation and gene expression. In particular, arsenic modulated genes which function as transcription factor, thereby affecting target genes which are known to play a role in lung cancer promotion and progression.]]>
Mon, 23 Nov 2015 00:00:00 PST
The expanding world of small RNAs in plants. Borges F, Martienssen RA
Nat Rev Mol Cell Biol (Dec 2015)

Plant genomes encode various small RNAs that function in distinct, yet overlapping, genetic and epigenetic silencing pathways. However, the abundance and diversity of small-RNA classes varies among plant species, suggesting coevolution between environmental adaptations and gene-silencing mechanisms. Biogenesis of small RNAs in plants is well understood, but we are just beginning to uncover their intricate regulation and activity. Here, we discuss the biogenesis of plant small RNAs, such as microRNAs, secondary siRNAs and heterochromatic siRNAs, and their diverse cellular and developmental functions, including in reproductive transitions, genomic imprinting and paramutation. We also discuss the diversification of small-RNA-directed silencing pathways through the expansion of RNA-dependent RNA polymerases, DICER proteins and ARGONAUTE proteins.]]>
Mon, 23 Nov 2015 00:00:00 PST
Integrating heterogeneous genomic data to accurately identify disease subtypes. Ren X, Fu H, Jin Q
BMC Med Genomics (2015)

High-throughput biotechnologies have been widely used to characterize clinical samples from various perspectives e.g., epigenomics, genomics and transcriptomics. However, because of the heterogeneity of these technologies and their outputs, individual analysis of the various types of data is hard to create a comprehensive view of disease subtypes. Integrative methods are of pressing need.]]>
Sat, 21 Nov 2015 00:00:00 PST
Lentiviral Vector Mediated Complementation Restored Fetal Viability but Not Placental hyperplasia in Plac1-Deficient Mice. Muto M, Fujihara Y, Tobita T, Kiyozumi D, Ikawa M
Biol Reprod (Nov 2015)

The X-linked Plac1 gene is maternally expressed in trophoblast cells during placentation and its disruption causes placental hyperplasia and intrauterine growth restriction. In contrast, Plac1 is also reported to be one of the upregulated genes in the hyperplastic placenta generated by nuclear transfer. However, the effect of over-expressed Plac1 on placental formation and function remained unaddressed. We complemented the Plac1 knockout placental dysfunction by lentiviral vector mediated placenta specific Plac1 transgene expression. Whereas fetal development and the morphology of maternal blood sinuses in the labyrinth zone improved, placental hyperplasia remained with an expanded the junctional zone that migrated and encroached into the labyrinth zone. Further experiments revealed that wild-type placenta with transgenically expressed Plac1 resulted in placental hyperplasia without the encroaching of junctional zone. Our findings suggest that Plac1 is involved in trophoblast cell proliferation, differentiation, and migration. Its proper expression is required for normal placentation and fetal development.]]>
Fri, 20 Nov 2015 00:00:00 PST
A DNMT3A2-HDAC2 Complex Is Essential for Genomic Imprinting and Genome Integrity in Mouse Oocytes. Ma P, de Waal E, Weaver JR, Bartolomei MS, Schultz RM
Cell Rep (Nov 2015)

Maternal genomic imprints are established during oogenesis. Histone deacetylases (HDACs) 1 and 2 are required for oocyte development in mouse, but their role in genomic imprinting is unknown. We find that Hdac1:Hdac2(-/-) double-mutant growing oocytes exhibit global DNA hypomethylation and fail to establish imprinting marks for Igf2r, Peg3, and Srnpn. Global hypomethylation correlates with increased retrotransposon expression and double-strand DNA breaks. Nuclear-associated DNMT3A2 is reduced in double-mutant oocytes, and injecting these oocytes with Hdac2 partially restores DNMT3A2 nuclear staining. DNMT3A2 co-immunoprecipitates with HDAC2 in mouse embryonic stem cells. Partial loss of nuclear DNMT3A2 and HDAC2 occurs in Sin3a(-/-) oocytes, which exhibit decreased DNA methylation of imprinting control regions for Igf2r and Srnpn, but not Peg3. These results suggest seminal roles of HDAC1/2 in establishing maternal genomic imprints and maintaining genomic integrity in oocytes mediated in part through a SIN3A complex that interacts with DNMT3A2.]]>
Fri, 20 Nov 2015 00:00:00 PST
HDACs Regulate miR-133a Expression in Pressure Overload-Induced Cardiac Fibrosis. Renaud L, Harris LG, Mani SK, Kasiganesan H, Chou JC, Baicu CF, Van Laer A, Akerman AW, Stroud RE, Jones JA, Zile MR, Menick DR
Circ Heart Fail (Nov 2015)

MicroRNAs (miRNAs) and histone deacetylases (HDACs) serve a significant role in the pathogenesis of a variety of cardiovascular diseases. The transcriptional regulation of miRNAs is poorly understood in cardiac hypertrophy. We investigated whether the expression of miR-133a is epigenetically regulated by class I and IIb HDACs during hypertrophic remodeling.]]>
Fri, 20 Nov 2015 00:00:00 PST
De novo DNA methylation through the 5'-segment of the H19 ICR maintains its imprint during early embryogenesis. Matsuzaki H, Okamura E, Takahashi T, Ushiki A, Nakamura T, Nakano T, Hata K, Fukamizu A, Tanimoto K
Development (Nov 2015)

Genomic imprinting is a major monoallelic gene expression regulatory mechanism in mammals, and depends on gamete-specific DNA methylation of specialized cis-regulatory elements called imprinting control regions (ICRs). Allele-specific DNA methylation of the ICRs is faithfully maintained at the imprinted loci throughout development, even in early embryos where genomes undergo extensive epigenetic reprogramming, including DNA demethylation, to acquire totipotency. We previously found that an ectopically introduced H19 ICR fragment in transgenic mice acquired paternal allele-specific methylation in the somatic cells of offspring, whereas it was not methylated in sperm, suggesting that its gametic and postfertilization modifications were separable events. We hypothesized that this latter activity might contribute to maintenance of the methylation imprint in early embryos. Here, we demonstrate that methylation of the paternally inherited transgenic H19 ICR commences soon after fertilization in a maternal DNMT3A- and DNMT3L-dependent manner. When its germline methylation was partially obstructed by insertion of insulator sequences, the endogenous paternal H19 ICR also exhibited postfertilization methylation. Finally, we refined the responsible sequences for this activity in transgenic mice and found that deletion of the 5' segment of the endogenous paternal H19 ICR decreased its methylation after fertilization and attenuated Igf2 gene expression. These results demonstrate that this segment of the H19 ICR is essential for its de novo postfertilization DNA methylation, and that this activity contributes to the maintenance of imprinted methylation at the endogenous H19 ICR during early embryogenesis.]]>
Fri, 20 Nov 2015 00:00:00 PST
Dynamic changes in histone modifications precede de novo DNA methylation in oocytes. Stewart KR, Veselovska L, Kim J, Huang J, Saadeh H, Tomizawa SI, Smallwood SA, Chen T, Kelsey G
Genes Dev (Nov 2015)

Erasure and subsequent reinstatement of DNA methylation in the germline, especially at imprinted CpG islands (CGIs), is crucial to embryogenesis in mammals. The mechanisms underlying DNA methylation establishment remain poorly understood, but a number of post-translational modifications of histones are implicated in antagonizing or recruiting the de novo DNA methylation complex. In mouse oogenesis, DNA methylation establishment occurs on a largely unmethylated genome and in nondividing cells, making it a highly informative model for examining how histone modifications can shape the DNA methylome. Using a chromatin immunoprecipitation (ChIP) and genome-wide sequencing (ChIP-seq) protocol optimized for low cell numbers and novel techniques for isolating primary and growing oocytes, profiles were generated for histone modifications implicated in promoting or inhibiting DNA methylation. CGIs destined for DNA methylation show reduced protective H3K4 dimethylation (H3K4me2) and trimethylation (H3K4me3) in both primary and growing oocytes, while permissive H3K36me3 increases specifically at these CGIs in growing oocytes. Methylome profiling of oocytes deficient in H3K4 demethylase KDM1A or KDM1B indicated that removal of H3K4 methylation is necessary for proper methylation establishment at CGIs. This work represents the first systematic study performing ChIP-seq in oocytes and shows that histone remodeling in the mammalian oocyte helps direct de novo DNA methylation events.]]>
Fri, 20 Nov 2015 00:00:00 PST
Exercise genomics-a paradigm shift is needed: a commentary. Bouchard C
Br J Sports Med (Dec 2015)

The overarching goal of exercise genomics is to illuminate exercise biology and behaviour in order to better understand the preventive and therapeutic values of exercise. An ancillary aim is to understand the role of genomic variation in human physical attributes and sports performance. The aim of this report is to briefly comment on the current status of exercise genetics and genomics and to suggest potential improvements to the research agenda and translational activities. First, the genomic features of interest to the biology of exercise are defined. Then, the limit of the current focus on common variants and their implications for exercise genomics is highlighted. The need for a major paradigm shift in exercise genomics research is discussed with an emphasis on study designs and appropriately powered studies as well as on more mechanistic and functional research. Finally, a summary of current practices in translational activities compared with what best practice demands is introduced. One suggestion is that the research portfolio of exercise genomics be composed of a larger fraction of experimental and mechanistic investigations and a smaller fraction of observational studies. It is also recommended that research should shift to unbiased exploration of the genome using all the power of genomics, epigenomics and transcriptomics in combination with large observational but preferably experimental study designs, including Mendelian randomisation. In all cases, emphasis on replications is of paramount importance. This represents an extraordinary challenge that can only be met with large-scale collaborative and multicentre research programmes.]]>
Fri, 20 Nov 2015 00:00:00 PST
Single-cell epigenomics: techniques and emerging applications. Schwartzman O, Tanay A
Nat Rev Genet (Dec 2015)

Epigenomics is the study of the physical modifications, associations and conformations of genomic DNA sequences, with the aim of linking these with epigenetic memory, cellular identity and tissue-specific functions. While current techniques in the field are characterizing the average epigenomic features across large cell ensembles, the increasing interest in the epigenetics within complex and heterogeneous tissues is driving the development of single-cell epigenomics. We review emerging single-cell methods for capturing DNA methylation, chromatin accessibility, histone modifications, chromosome conformation and replication dynamics. Together, these techniques are rapidly becoming a powerful tool in studies of cellular plasticity and diversity, as seen in stem cells and cancer.]]>
Fri, 20 Nov 2015 00:00:00 PST
Epigenomics: Sex matters. Koch L
Nat Rev Genet (Dec 2015)

Fri, 20 Nov 2015 00:00:00 PST
Transgenerational epigenetic inheritance of diabetes risk as a consequence of early nutritional imbalances. Jimenez-Chillaron JC, Ramon-Krauel M, Ribo S, Diaz R
Proc Nutr Soc (Nov 2015)

In today's world, there is an unprecedented rise in the prevalence of chronic metabolic diseases, including obesity, insulin resistance and type 2 diabetes (T2D). The pathogenesis of T2D includes both genetic and environmental factors, such as excessive energy intake and physical inactivity. It has recently been suggested that environmental factors experienced during early stages of development, including the intrauterine and neonatal periods, might play a major role in predisposing individuals to T2D. Furthermore, several studies have shown that such early environmental conditions might even contribute to disease risk in further generations. In this review, we summarise recent data describing how parental nutrition during development increases the risk of diabetes in the offspring. We also discuss the potential mechanisms underlying transgenerational inheritance of metabolic disease, with particular emphasis on epigenetic mechanisms.]]>
Tue, 17 Nov 2015 00:00:00 PST
TRIM28 Controls Genomic Imprinting through Distinct Mechanisms during and after Early Genome-wide Reprogramming. Alexander KA, Wang X, Shibata M, Clark AG, García-García MJ
Cell Rep (Nov 2015)

Genomic imprinting depends on the establishment and maintenance of DNA methylation at imprinting control regions. However, the mechanisms by which these heritable marks influence allele-specific expression are not fully understood. By analyzing maternal, zygotic, maternal-zygotic, and conditional Trim28 mutants, we found that the transcription factor TRIM28 controls genomic imprinting through distinct mechanisms at different developmental stages. During early genome-wide reprogramming, both maternal and zygotic TRIM28 are required for the maintenance of methylation at germline imprints. However, in conditional Trim28 mutants, Gtl2-imprinted gene expression was lost despite normal methylation levels at the germline IG-DMR. These results provide evidence that TRIM28 controls imprinting after early embryonic reprogramming through a mechanism other than the maintenance of germline imprints. Additionally, our finding that secondary imprints were hypomethylated in TRIM28 mutants uncovers a requirement of TRIM28 after genome-wide reprogramming for interpreting germline imprints and regulating DNA methylation at imprinted gene promoters.]]>
Sat, 14 Nov 2015 00:00:00 PST
Identification of Differentially Methylated Loci Using Wavelet-Based Functional Mixed Models. Lee W, Morris JS
Bioinformatics (Nov 2015)

DNA methylation is a key epigenetic modification that can modulate gene expression. Over the past decade, a lot of studies have focused on profiling DNA methylation and investigating its alterations in complex diseases such as cancer. While early studies were mostly restricted to CpG islands or promoter regions, recent findings indicate that many of important DNA methylation changes can occur in other regions and DNA methylation needs to be examined on a genome-wide scale. In this article, we apply the wavelet-based functional mixed model methodology to analyze the high-throughput methylation data for identifying differentially methylated loci across the genome. Contrary to many commonly-used methods that model probes independently, this framework accommodates spatial correlations across the genome through basis function modeling as well as correlations between samples through functional random effects, which allows it to be applied to many different settings and potentially leads to more power in detection of differential methylation.]]>
Thu, 12 Nov 2015 00:00:00 PST
Functions of TET Proteins in Hematopoietic Transformation. Han JA, An J, Ko M
Mol Cells (Nov 2015)

DNA methylation is a well-characterized epigenetic modification that plays central roles in mammalian development, genomic imprinting, X-chromosome inactivation and silencing of retrotransposon elements. Aberrant DNA methylation pattern is a characteristic feature of cancers and associated with abnormal expression of oncogenes, tumor suppressor genes or repair genes. Ten-eleven-translocation (TET) proteins are recently characterized dioxygenases that catalyze progressive oxidation of 5-methylcytosine to produce 5-hydroxymethylcytosine and further oxidized derivatives. These oxidized methylcytosines not only potentiate DNA demethylation but also behave as independent epigenetic modifications per se. The expression or activity of TET proteins and DNA hydroxymethylation are highly dysregulated in a wide range of cancers including hematologic and non-hematologic malignancies, and accumulating evidence points TET proteins as a novel tumor suppressor in cancers. Here we review DNA demethylation-dependent and -independent functions of TET proteins. We also describe diverse TET loss-of-function mutations that are recurrently found in myeloid and lymphoid malignancies and their potential roles in hematopoietic transformation. We discuss consequences of the deficiency of individual Tet genes and potential compensation between different Tet members in mice. Possible mechanisms underlying facilitated oncogenic transformation of TET-deficient hematopoietic cells are also described. Lastly, we address non-mutational mechanisms that lead to suppression or inactivation of TET proteins in cancers. Strategies to restore normal 5mC oxidation status in cancers by targeting TET proteins may provide new avenues to expedite the development of promising anti-cancer agents.]]>
Tue, 10 Nov 2015 00:00:00 PST
Modeling Genomic Imprinting Disorders Using Induced Pluripotent Stem Cells. Chamberlain SJ, Germain ND, Chen PF, Hsiao JS, Glatt-Deeley H
Methods Mol Biol (2016)

Induced pluripotent stem cell (iPSC) technology has allowed for the invaluable modeling of many genetic disorders including disorders associated with genomic imprinting. Genomic imprinting involves differential DNA and histone methylation and results in allele-specific gene expression. Most of the epigenetic marks in somatic cells are erased and reestablished during the process of reprogramming into iPSCs. Therefore, in generating models of disorders associated with genomic imprinting, it is important to verify that the imprinting status and allele-specific gene expression patterns of the parental somatic cells are maintained in their derivative iPSCs. Here, we describe three techniques: DNA methylation analysis, allele-specific PCR, and RNA FISH, which we use to analyze genomic imprinting in iPSC models of neurogenetic disorders involving copy number variations of the chromosome 15q11-q13 region.]]>
Mon, 09 Nov 2015 00:00:00 PST
A multi-omic analysis of human naïve CD4+ T cells. Mitchell CJ, Getnet D, Kim MS, Manda SS, Kumar P, Huang TC, Pinto SM, Nirujogi RS, Iwasaki M, Shaw PG, Wu X, Zhong J, Chaerkady R, Marimuthu A, Muthusamy B, Sahasrabuddhe NA, Raju R, Bowman C, Danilova L, Cutler J, Kelkar DS, Drake CG, Prasad TS, Marchionni L, Murakami PN, Scott AF, Shi L, Thierry-Mieg J, Thierry-Mieg D, Irizarry R, Cope L, Ishihama Y, Wang C, Gowda H, Pandey A
BMC Syst Biol (2015)

Cellular function and diversity are orchestrated by complex interactions of fundamental biomolecules including DNA, RNA and proteins. Technological advances in genomics, epigenomics, transcriptomics and proteomics have enabled massively parallel and unbiased measurements. Such high-throughput technologies have been extensively used to carry out broad, unbiased studies, particularly in the context of human diseases. Nevertheless, a unified analysis of the genome, epigenome, transcriptome and proteome of a single human cell type to obtain a coherent view of the complex interplay between various biomolecules has not yet been undertaken. Here, we report the first multi-omic analysis of human primary naïve CD4+ T cells isolated from a single individual.]]>
Fri, 06 Nov 2015 00:00:00 PST
Prader-Willi syndrome: a review of clinical, genetic, and endocrine findings. Angulo MA, Butler MG, Cataletto ME
J Endocrinol Invest (Dec 2015)

Prader-Willi syndrome (PWS) is a multisystemic complex genetic disorder caused by lack of expression of genes on the paternally inherited chromosome 15q11.2-q13 region. There are three main genetic subtypes in PWS: paternal 15q11-q13 deletion (65-75 % of cases), maternal uniparental disomy 15 (20-30 % of cases), and imprinting defect (1-3 %). DNA methylation analysis is the only technique that will diagnose PWS in all three molecular genetic classes and differentiate PWS from Angelman syndrome. Clinical manifestations change with age with hypotonia and a poor suck resulting in failure to thrive during infancy. As the individual ages, other features such as short stature, food seeking with excessive weight gain, developmental delay, cognitive disability and behavioral problems become evident. The phenotype is likely due to hypothalamic dysfunction, which is responsible for hyperphagia, temperature instability, high pain threshold, hypersomnia and multiple endocrine abnormalities including growth hormone and thyroid-stimulating hormone deficiencies, hypogonadism and central adrenal insufficiency. Obesity and its complications are the major causes of morbidity and mortality in PWS.]]>
Tue, 03 Nov 2015 00:00:00 PST
Restricted development of mouse triploid fetuses with disorganized expression of imprinted genes. Yamazaki W, Takahashi M, Kawahara M
Zygote (Dec 2015)

Eukaryotic species commonly contain a diploid complement of chromosomes. The diploid state appears to be advantageous for mammals because it enables sexual reproduction and facilitates genetic recombination. Nonetheless, the effects of DNA ploidy on mammalian ontogeny have yet to be understood. The present study shows phenotypic features and expression patterns of imprinted genes in tripronucleate diandric and digynic triploid (DAT and DGT) mouse fetuses on embryonic day 10.5 (E10.5). Measurement of crown-rump length revealed that the length of DGT fetuses (1.87 ± 0.13 mm; mean ± standard error of the mean) was much smaller than that of diploid fetuses (4.81 ± 0.05 mm). However, no significant difference was observed in the crown-rump length between diploid and DAT fetuses (3.86 ± 0.43 mm). In DGT fetuses, the expression level of paternally expressed genes, Igf2, Dlk1, Ndn, and Peg3, remained significantly reduced and that of maternally expressed genes, Igf2r and Grb10, increased. Additionally, in DAT fetuses, the Igf2 mRNA expression level was approximately twice that in diploid fetuses, as expected. These results provide the first demonstration that imprinted genes in mouse triploid fetuses show distinctive expression patterns independent of the number of parental-origin haploid sets. These data suggest that both DNA ploidy and asymmetrical functions of parental genomes separately influence mammalian ontogeny.]]>
Tue, 27 Oct 2015 00:00:00 PDT
Epigenetics in the Vascular Endothelium: Looking From a Different Perspective in the Epigenomics Era. Yan MS, Marsden PA
Arterioscler Thromb Vasc Biol (Nov 2015)

Cardiovascular diseases are commonly thought to be complex, non-Mendelian diseases that are influenced by genetic and environmental factors. A growing body of evidence suggests that epigenetic pathways play a key role in vascular biology and might be involved in defining and transducing cardiovascular disease inheritability. In this review, we argue the importance of epigenetics in vascular biology, especially from the perspective of endothelial cell phenotype. We highlight and discuss the role of epigenetic modifications across the transcriptional unit of protein-coding genes, especially the role of intragenic chromatin modifications, which are underappreciated and not well characterized in the current era of genome-wide studies. Importantly, we describe the practical application of epigenetics in cardiovascular disease therapeutics.]]>
Thu, 22 Oct 2015 00:00:00 PDT