'; ?> 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 Tue, 23 Aug 2016 13:33:36 PDT Tue, 23 Aug 2016 13:33:36 PDT jirtle@radonc.duke.edu james001@jirtle.com Emerging concepts of epigenetic dysregulation in hematological malignancies. Ntziachristos P, Abdel-Wahab O, Aifantis I
Nat Immunol (Sep 2016)

The past decade brought a revolution in understanding of the structure, topology and disease-inducing lesions of RNA and DNA, fueled by unprecedented progress in next-generation sequencing. This technological revolution has also affected understanding of the epigenome and has provided unique opportunities for the analysis of DNA and histone modifications, as well as the first map of the non-protein-coding genome and three-dimensional (3D) chromosomal interactions. Overall, these advances have facilitated studies that combine genetic, transcriptomics and epigenomics data to address a wide range of issues ranging from understanding the role of the epigenome in development to targeting the transcription of noncoding genes in human cancer. Here we describe recent insights into epigenetic dysregulation characteristic of the malignant differentiation of blood stem cells based on studies of alterations that affect epigenetic complexes, enhancers, chromatin, long noncoding RNAs (lncRNAs), RNA splicing, nuclear topology and the 3D conformation of chromatin.]]>
Sat, 20 Aug 2016 00:00:00 PDT
Increaseddosage of the imprinted Ascl2 gene restrains two key endocrine lineages of the mouse placenta. Tunster SJ, McNamara GI, Creeth HD, John RM
Dev Biol (Aug 2016)

Imprintedgenes are expressed primarily from one parental allele by virtue of a germ line epigenetic process. Achaete-scute complex homolog 2(Ascl2aka Mash2)is a maternally expressed imprinted gene that plays a key role in placental and intestinal development. Loss-of-function of Ascl2results in an expansion of the parietal trophoblast giant cell (P-TGC) lineage, an almost complete loss of Trophoblast specific protein alpha (Tpbpa) positive cells in the ectoplacental cone and embryonic failure by E10.5.Tpbpa expression marks the progenitors of some P-TGCs, two additional trophoblast giant cell lineages (spiral artery and canal), the spongiotrophoblast and the glycogen cell lineage. Using a transgenic model, here we show that elevated expression of Ascl2reduced the number of P-TGC cells by 40%.Elevated Ascl2also resulted in a marked loss of the spongiotrophoblast and a substantial mislocalisation of glycogen cells into the labyrinth. In addition, Ascl2-Tg placenta contained considerably more placental glycogen than wild type. Glycogen cells are normally located within the junctional zone in close contact with spongiotrophoblast cells, before migrating through the P-TGC layer into the maternal decidua late in gestation where their stores of glycogen are released. The failure of glycogen cells to release their stores of glycogen may explain both the inappropriate accumulation of glycogen and fetal growth restriction observed late in gestation in this model. In addition, using in a genetic cross we provide evidence that that Ascl2 requires the activity of a second maternally expressed imprinted gene, Pleckstrin homology-like domain, family a, member 2 (Phlda2) to limit the expansion of the spongiotrophoblast. This "belts and braces" approach demonstrates the importance of genomic imprinting in regulating the size of the placental endocrine compartment for optimal placental development and fetal growth.]]>
Sat, 20 Aug 2016 00:00:00 PDT
Single-cell genome-wide studies give new insight into nongenetic cell-to-cell variability in animals. Golov AK, Razin SV, Gavrilov AA
Histochem Cell Biol (Sep 2016)

Huge numbers of cells form an adult animal body, ranging from several thousands in Placozoa and small nematodes to many billions in mammals. Cells are classified into separate groups known as cell types by their morphological and biochemical features. Six to several hundreds of spatially ordered cell types are recognized in different animals. This complex organization develops from one cell, a zygote, during ontogeny, and its dynamic equilibrium is often maintained in the adult body. One of the key challenges in biology is to understand the mechanisms that sustain the reproducible development of a complex ordered cell ensemble such as the animal body from a single cell. How cells with identical genomes stably maintain one of the numerous possible phenotypes? How the cell differentiation lineage is selected during development? What genes play a key role in maintaining cell identity, and how do they determine expression of other genes characteristic of the relevant cell type? How does the basically stochastic nature of transcription in an isolated cell affect the stability of cell identity, the selection of a cell lineage, and the variability of cell responses to external stimuli? Better-grounded answers to these questions have become possible with recent progress in single-cell genome-wide analysis techniques, which combine the high throughput of biochemical methods and the differential nature of microscopy. The techniques are still in their infancy, and their further development will certainly revolutionize many fields of life sciences and, in particular, developmental biology. Here, we summarize the main results that have been obtained in single-cell genome-wide analyses and describe the nongenetic cell-to-cell variability in animals.]]>
Fri, 19 Aug 2016 00:00:00 PDT
Drug metabolism and disposition diversity of Ranunculales phytometabolites: a systems perspective. Hao da C, Yang L
Expert Opin Drug Metab Toxicol (Sep 2016)

Although investigations in metabolism and pharmacokinetics of Ranunculales phytometabolites are booming, data obtained from human and animal studies have not been summarized as a whole to outline current trends and to predict future development.]]>
Fri, 19 Aug 2016 00:00:00 PDT
A modified MS-PCR approach to diagnose patients with Prader-Willi and Angelman syndrome. Dos Santos JF, Mota LR, Rocha PH, Ferreira de Lima RL
Mol Biol Rep (Aug 2016)

Prader-Willi (PWS) and Angelman (AS) syndromes are clinically distinct neurodevelopmental genetic diseases with multiple phenotypic manifestations. They are one of the most common genetic syndromes caused by non-Mendelian inheritance in the form of genomic imprinting, and can be attributable to the loss of gene expression due to imprinting within the chromosomal region 15q11-q13. Clinical diagnosis of PWS and AS is challenging, and the use of molecular and cytomolecular studies is recommended to help in determining the diagnosis of these conditions. The methylation analysis is a sensible approach; however there are several techniques for this purpose, such as the methylation-sensitive polymerase chain reaction (MS-PCR). This study aims to optimize the MS-PCR assay for the diagnosis of potential PWS and AS patients using DNA modified by sodium bisulfite. We used the MS-PCR technique of PCR described by Kosaki et al. (1997) adapted with betaine. All different concentrations of betaine used to amplify the methylated and unmethylated chromosomal region 15q11-q13 on the gene SNRPN showed amplification results, which increased proportionally to the concentration of betaine. The methylation analysis is a technically robust and reproducible screening method for PWS and AS. The MS-PCR assures a faster, cheaper and more efficient method for the primary diagnosis of the SNRPN gene in cases with PWS and AS, and may detect all of the three associated genetic abnormalities: deletion, uniparental disomy or imprinting errors.]]>
Thu, 18 Aug 2016 00:00:00 PDT
Sequencing-based diagnostics for pediatric genetic diseases: progress and potential. Abou Tayoun AN, Krock B, Spinner NB
Expert Rev Mol Diagn (Aug 2016)

The last two decades have witnessed revolutionary changes in clinical diagnostics, fueled by the Human Genome Project and advances in high throughput, Next Generation Sequencing (NGS). We review the current state of sequencing-based pediatric diagnostics, associated challenges, and future prospects.]]>
Wed, 17 Aug 2016 00:00:00 PDT
The Influence of Polyploidy and Genome Composition on Genomic Imprinting in Mice. Yamazaki W, Amano T, Bai H, Takahashi M, Kawahara M
J Biol Chem (Aug 2016)

Genomic imprinting is an epigenetic mechanism that switches the expression of imprinted genes involved in normal embryonic growth and development in a parent-of-origin-specific manner. Changes in DNA methylation statuses from polyploidization are a well-characterized epigenetic modification in plants. However, how changes in ploidy affect both imprinted gene expression and methylation status in mammals remains unclear. To address this, we used quantitative real-time PCR to analyze expression levels of imprinted genes in mouse tetraploid fetuses. We used bisulfite sequencing to assess the methylation statuses of differentially methylated regions (DMRs) that regulate imprinted gene expression in triploid and tetraploid fetuses. The 9 imprinted genes H19, Gtl2, Dlk1, Igf2r, Grb10, Zim1, Peg3, Ndn, and Ipw were all unregulated, in particular, the expression of Zim1 was more than 10-fold higher and the expression of Ipw was repressed in tetraploid fetuses. The methylation statuses of 4 DMRs H19, IG, Igf2r, and Snrpn in tetraploid and triploid fetuses were similar to those in diploid fetuses. We also performed allele-specific RT-PCR sequencing to determine the alleles expressing the 3 imprinted genes Igf2, Gtl2, and Dlk1 in tetraploid fetuses. These 3 imprinted genes showed monoallelic expression in a parent-of-origin-specific manner. Expression of non-imprinted genes regulating neural cell development significantly decreased in tetraploid fetuses, which might have been associated with unregulated imprinted gene expression. This study provides the first detailed analysis of genomic imprinting in tetraploid fetuses, suggesting that imprinted gene expression is disrupted but DNA methylation statuses of DMRs are stable following changes in ploidy in mammals.]]>
Wed, 17 Aug 2016 00:00:00 PDT
Teratozoospermia and asthenozoospermia are associated with specific epigenetic signatures. Jenkins TG, Aston KI, Hotaling JM, Shamsi MB, Simon L, Carrell DT
Andrology (Sep 2016)

Semen analysis is commonly used as a tool to assess the fertility potential of a male, despite its relatively low predictive power. In this study, we have assessed associations between semen analysis findings (low count, low motility, low viability, poor sperm penetration assay results, poor morphology, and increased DNA damage) and DNA methylation patterns in mature spermatozoa. DNA methylation patterns in the mature spermatozoa are thought to be indicative of patterns in the adult germline stem cells and may offer insight into potential perturbations to cellular pathways involved in spermatogenesis. In this study, sperm DNA methylation at >480,000 CpGs was assessed in 94 men using the Illumina 450k HumanMethylation Array and compared to standard measures of sperm quality. We did not identify any global changes to methylation profiles that were associated with reduced semen parameters. Similarly, we found no significant difference in methylation variability that was associated with any abnormal semen analysis parameter, although sperm displaying abnormal parameters tended to have an increased coefficient of variability, suggesting that, in some samples, this may be a contributing factor. Analysis of methylation at single CpGs and genomic regions did identify associations for low viability and low motility, and to a smaller extent, low count. Interestingly, based on GO Term analysis, differentially methylated regions associated with low viability were over-represented in regions important in meiosis, spermatogenesis, and genomic imprinting. These results suggest that while there are not global alterations to the sperm methylome associated with semen abnormalites, some viability associated regional alterations do exist that may be indicative of perturbed cellular pathways during spermatogenesis.]]>
Wed, 17 Aug 2016 00:00:00 PDT
Cross-species Conservation of context-specific networks. Pesch R, Zimmer R
BMC Syst Biol (2016)

Many large data compendia on context-specific high-throughput genomic and regulatory data have been made available by international research consortia such as ENCODE, TCGA, and Epigenomics Roadmap. The use of these resources is impaired by the sheer size of the available big data and big metadata. Many of these context-specific data can be modeled as data derived regulatory networks (DDRNs) representing the complex and complicated interactions between transcription factors and target genes. These DDRNs are useful for the understanding of regulatory mechanisms and helpful for interpreting biomedical data.]]>
Wed, 17 Aug 2016 00:00:00 PDT
Complete in vitro generation of fertile oocytes from mouse primordial germ cells. Morohaku K, Tanimoto R, Sasaki K, Kawahara-Miki R, Kono T, Hayashi K, Hirao Y, Obata Y
Proc Natl Acad Sci U S A (Aug 2016)

Reconstituting gametogenesis in vitro is a key goal for reproductive biology and regenerative medicine. Successful in vitro reconstitution of primordial germ cells and spermatogenesis has recently had a significant effect in the field. However, recapitulation of oogenesis in vitro remains unachieved. Here we demonstrate the first reconstitution, to our knowledge, of the entire process of mammalian oogenesis in vitro from primordial germ cells, using an estrogen-receptor antagonist that promotes normal follicle formation, which in turn is crucial for supporting oocyte growth. The fundamental events in oogenesis (i.e., meiosis, oocyte growth, and genomic imprinting) were reproduced in the culture system. The most rigorous evidence of the recapitulation of oogenesis was the birth of fertile offspring, with a maximum of seven pups obtained from a cultured gonad. Moreover, cryopreserved gonads yielded functional oocytes and offspring in this culture system. Thus, our in vitro system will enable both innovative approaches for a deeper understanding of oogenesis and a new avenue to create and preserve female germ cells.]]>
Thu, 11 Aug 2016 00:00:00 PDT
Integrated epigenomics analysis reveals a DNA methylation panel for endometrial cancer detection using cervical scrapings. Huang RL, Su PH, Liao YP, Wu TI, Hsu YT, Lin WY, Wang HC, Weng YJ, Ou YC, Huang TH, Lai HC
Clin Cancer Res (Aug 2016)

Endometrial cancer (EC) is a common gynecological cancer whose incidence is increasing annually worldwide. Current methods to detect EC are unreliable and biomarkers are unsatisfactory for screening. Cervical scrapings were reported as a potential source of material for molecular testing. DNA methylation is a promising cancer biomarker, but limited use for detecting EC.]]>
Wed, 10 Aug 2016 00:00:00 PDT
Impulsive choices in mice lacking imprinted Nesp55. Dent CL, Humby T, Lewis K, Plagge A, Fischer-Colbrie R, Wilkins JF, Wilkinson LS, Isles AR
Genes Brain Behav (Aug 2016)

Genomic imprinting is the process whereby germline epigenetic events lead to parent-of-origin specific monallelic expression of a number of key mammalian genes. The imprinted gene Nesp is expressed from the maternal allele only and encodes for Nesp55 protein. In the brain Nesp55 is found predominately in discrete areas of the hypothalamus and midbrain. Previously, we have shown that loss of Nesp55 gives rise to alterations in novelty-related behavior. Here we extend these findings and demonstrate, using the Nesp(m/+) mouse model, that loss of Nesp55 leads to impulsive choices as measured by a delayed-reinforcement task, whereby Nesp(m/+) mice were less willing to wait for a delayed, larger reward, preferring instead to choose an immediate, smaller reward. These effects were highly specific as performance in another component of impulsive behavior, the ability to stop a response once started as assayed in the stop-signal reaction time task, was equivalent to controls. We also showed changes in the serotonin system, a key neurotransmitter pathway mediating impulsive behavior. First, we demonstrated that Nesp55 is co-localised with serotonin and then went on to show that in midbrain regions there were reductions in mRNA expression of the serotonin specific genes Tph2 and Slc6a4, but not the dopamine specific gene Th in Nesp(m/+) mice; suggesting an altered serotonergic system could contribute, in part, to the changes in impulsive behavior. These data provide a novel mode of action for genomic imprinting in the brain and may have implications for pathological conditions characterized by maladaptive response control.]]>
Wed, 10 Aug 2016 00:00:00 PDT
A Simplified, Langendorff-Free Method for Concomitant Isolation of Viable Cardiac Myocytes and Non-Myocytes from the Adult Mouse Heart. Ackers-Johnson M, Li PY, Holmes AP, O'Brien SM, Pavlovic D, Foo RS
Circ Res (Aug 2016)

Cardiovascular disease represents a global pandemic. The advent of and recent advances in mouse genomics, epigenomics and transgenics offer ever greater potential for powerful avenues of research. However, progress is often constrained by unique complexities associated with the isolation of viable myocytes from the adult mouse heart. Current protocols rely on retrograde aortic perfusion using specialised Langendorff apparatus, which poses considerable logistical and technical barriers to researchers, and demands extensive training investment.]]>
Tue, 09 Aug 2016 00:00:00 PDT
Angelman syndrome-derived neurons display late onset of paternal UBE3A silencing. Stanurova J, Neureiter A, Hiber M, de Oliveira Kessler H, Stolp K, Goetzke R, Klein D, Bankfalvi A, Klump H, Steenpass L
Sci Rep (2016)

Genomic imprinting is an epigenetic phenomenon resulting in parent-of-origin-specific gene expression that is regulated by a differentially methylated region. Gene mutations or failures in the imprinting process lead to the development of imprinting disorders, such as Angelman syndrome. The symptoms of Angelman syndrome are caused by the absence of functional UBE3A protein in neurons of the brain. To create a human neuronal model for Angelman syndrome, we reprogrammed dermal fibroblasts of a patient carrying a defined three-base pair deletion in UBE3A into induced pluripotent stem cells (iPSCs). In these iPSCs, both parental alleles are present, distinguishable by the mutation, and express UBE3A. Detailed characterization of these iPSCs demonstrated their pluripotency and exceptional stability of the differentially methylated region regulating imprinted UBE3A expression. We observed strong induction of SNHG14 and silencing of paternal UBE3A expression only late during neuronal differentiation, in vitro. This new Angelman syndrome iPSC line allows to study imprinted gene regulation on both parental alleles and to dissect molecular pathways affected by the absence of UBE3A protein.]]>
Wed, 03 Aug 2016 00:00:00 PDT
ATP-binding cassette transmembrane transporters and their epigenetic control in cancer: an overview. Arrigoni E, Galimberti S, Petrini M, Danesi R, Di Paolo A
Expert Opin Drug Metab Toxicol (Aug 2016)

Members of the ATP-binding cassette (ABC) transmembrane transporters control the passage of several substrates across cell membranes, including drugs. This means that ABC transporters may exert a significant influence on the kinetics and dynamics of pharmacological agents, being responsible for the occurrence of multidrug-resistant (MDR) phenotype. Pharmacogenetic analyses have shed light on gene expression and polymorphisms as possible markers predictive of transporter activity. However, a non-negligible part of the variability in drug pharmacokinetics and pharmacodynamics still remains. Further research has demonstrated that different epigenetic mechanisms exert a coordinated control over ABC genes, and on the corresponding MDR phenotype.]]>
Wed, 03 Aug 2016 00:00:00 PDT
The Many Roles of BAF (mSWI/SNF) and PBAF Complexes in Cancer. Hodges C, Kirkland JG, Crabtree GR
Cold Spring Harb Perspect Med (2016)

During the last decade, a host of epigenetic mechanisms were found to contribute to cancer and other human diseases. Several genomic studies have revealed that ∼20% of malignancies have alterations of the subunits of polymorphic BRG-/BRM-associated factor (BAF) and Polybromo-associated BAF (PBAF) complexes, making them among the most frequently mutated complexes in cancer. Recurrent mutations arise in genes encoding several BAF/PBAF subunits, including ARID1A, ARID2, PBRM1, SMARCA4, and SMARCB1 These subunits share some degree of conservation with subunits from related adenosine triphosphate (ATP)-dependent chromatin remodeling complexes in model organisms, in which a large body of work provides insight into their roles in cancer. Here, we review the roles of BAF- and PBAF-like complexes in these organisms, and relate these findings to recent discoveries in cancer epigenomics. We review several roles of BAF and PBAF complexes in cancer, including transcriptional regulation, DNA repair, and regulation of chromatin architecture and topology. More recent results highlight the need for new techniques to study these complexes.]]>
Tue, 02 Aug 2016 00:00:00 PDT
GenomeRunner web server: regulatory similarity and differences define the functional impact of SNP sets. Dozmorov MG, Cara LR, Giles CB, Wren JD
Bioinformatics (Aug 2016)

The growing amount of regulatory data from the ENCODE, Roadmap Epigenomics and other consortia provides a wealth of opportunities to investigate the functional impact of single nucleotide polymorphisms (SNPs). Yet, given the large number of regulatory datasets, researchers are posed with a challenge of how to efficiently utilize them to interpret the functional impact of SNP sets.]]>
Sat, 30 Jul 2016 00:00:00 PDT
Chromatin and epigenetics in all their states: Meeting report of the first conference on Epigenetic and Chromatin Regulation of Plant Traits - January 14 - 15, 2016 - Strasbourg, France. Bey T, Jamge S, Klemme S, Komar DN, Le Gall S, Mikulski P, Schmidt M, Zicola J, Berr A
Epigenetics (Aug 2016)

In January 2016, the first Epigenetic and Chromatin Regulation of Plant Traits conference was held in Strasbourg, France. An all-star lineup of speakers, a packed audience of 130 participants from over 20 countries, and a friendly scientific atmosphere contributed to make this conference a meeting to remember. In this article we summarize some of the new insights into chromatin, epigenetics, and epigenomics research and highlight nascent ideas and emerging concepts in this exciting area of research.]]>
Sat, 30 Jul 2016 00:00:00 PDT
Fine-scale mapping of 8q24 locus identifies multiple independent risk variants for breast cancer. Shi J, Zhang Y, Zheng W, Michailidou K, Ghoussaini M, Bolla MK, Wang Q, Dennis J, Lush M, Milne RL, Shu XO, Beesley J, Kar S, Andrulis IL, Anton-Culver H, Arndt V, Beckmann MW, Zhao Z, Guo X, Benitez J, Beeghly-Fadiel A, Blot W, Bogdanova NV, Bojesen SE, Brauch H, Brenner H, Brinton L, Broeks A, Brüning T, Burwinkel B, Cai H, Canisius S, Chang-Claude J, Choi JY, Couch FJ, Cox A, Cross SS, Czene K, Darabi H, Devilee P, Droit A, Dork T, Fasching PA, Fletcher O, Flyger H, Fostira F, Gaborieau V, García-Closas M, Giles GG, Grip M, Guenel P, Haiman CA, Hamann U, Hartman M, Miao H, Hollestelle A, Hopper JL, Hsiung CN,  , Ito H, Jakubowska A, Johnson N, Torres D, Kabisch M, Kang D, Khan S, Knight JA, Kosma VM, Lambrechts D, Li J, Lindblom A, Lophatananon A, Lubinski J, Mannermaa A, Manoukian S, Le Marchand L, Margolin S, Marme F, Matsuo K, McLean C, Meindl A, Muir K, Neuhausen SL, Nevanlinna H, Nord S, Børresen-Dale AL, Olson JE, Orr N, van den Ouweland AM, Peterlongo P, Choudary Putti T, Rudolph A, Sangrajrang S, Sawyer EJ, Schmidt MK, Schmutzler RK, Shen CY, Hou MF, Shrubsole MJ, Southey MC, Swerdlow A, Hwang Teo S, Thienpont B, Toland AE, Tollenaar RA, Tomlinson I, Truong T, Tseng CC, Wen W, Winqvist R, Wu AH, Har Yip C, Zamora PM, Zheng Y, Floris G, Cheng CY, Hooning MJ, Martens JW, Seynaeve C, Kristensen VN, Hall P, Pharoah PD, Simard J, Chenevix-Trench G, Dunning AM, Antoniou AC, Easton DF, Cai Q, Long J
Int J Cancer (Sep 2016)

Previous genome-wide association studies among women of European ancestry identified two independent breast cancer susceptibility loci represented by single nucleotide polymorphisms (SNPs) rs13281615 and rs11780156 at 8q24. A fine-mapping study across 2.06 Mb (chr8:127,561,724-129,624,067, hg19) in 55,540 breast cancer cases and 51,168 controls within the Breast Cancer Association Consortium was conducted. Three additional independent association signals in women of European ancestry, represented by rs35961416 (OR = 0.95, 95% CI = 0.93-0.97, conditional p = 5.8 × 10(-6) ), rs7815245 (OR = 0.94, 95% CI = 0.91-0.96, conditional p = 1.1 × 10(-6) ) and rs2033101 (OR = 1.05, 95% CI = 1.02-1.07, conditional p = 1.1 × 10(-4) ) were found. Integrative analysis using functional genomic data from the Roadmap Epigenomics, the Encyclopedia of DNA Elements project, the Cancer Genome Atlas and other public resources implied that SNPs rs7815245 in Signal 3, and rs1121948 in Signal 5 (in linkage disequilibrium with rs11780156, r(2)  = 0.77), were putatively functional variants for two of the five independent association signals. The results highlighted multiple 8q24 variants associated with breast cancer susceptibility in women of European ancestry.]]>
Sat, 09 Jul 2016 00:00:00 PDT
Nongenomic regulation of gene expression. Iglesias-Platas I, Monk D
Curr Opin Pediatr (Aug 2016)

The purpose of this review is to highlight the recent advances in epigenetic regulation and chromatin biology for a better understanding of gene regulation related to human disease.]]>
Thu, 07 Jul 2016 00:00:00 PDT