'; ?> 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 Fri, 30 Jan 2015 10:54:32 PST Fri, 30 Jan 2015 10:54:32 PST jirtle@radonc.duke.edu james001@jirtle.com Structural insight into autoinhibition and histone H3-induced activation of DNMT3A. Guo X, Wang L, Li J, Ding Z, Xiao J, Yin X, He S, Shi P, Dong L, Li G, Tian C, Wang J, Cong Y, Xu Y
Nature (Jan 2015)

DNA methylation is an important epigenetic modification that is essential for various developmental processes through regulating gene expression, genomic imprinting, and epigenetic inheritance. Mammalian genomic DNA methylation is established during embryogenesis by de novo DNA methyltransferases, DNMT3A and DNMT3B, and the methylation patterns vary with developmental stages and cell types. DNA methyltransferase 3-like protein (DNMT3L) is a catalytically inactive paralogue of DNMT3 enzymes, which stimulates the enzymatic activity of Dnmt3a. Recent studies have established a connection between DNA methylation and histone modifications, and revealed a histone-guided mechanism for the establishment of DNA methylation. The ATRX-DNMT3-DNMT3L (ADD) domain of Dnmt3a recognizes unmethylated histone H3 (H3K4me0). The histone H3 tail stimulates the enzymatic activity of Dnmt3a in vitro, whereas the molecular mechanism remains elusive. Here we show that DNMT3A exists in an autoinhibitory form and that the histone H3 tail stimulates its activity in a DNMT3L-independent manner. We determine the crystal structures of DNMT3A-DNMT3L (autoinhibitory form) and DNMT3A-DNMT3L-H3 (active form) complexes at 3.82 and 2.90 Å resolution, respectively. Structural and biochemical analyses indicate that the ADD domain of DNMT3A interacts with and inhibits enzymatic activity of the catalytic domain (CD) through blocking its DNA-binding affinity. Histone H3 (but not H3K4me3) disrupts ADD-CD interaction, induces a large movement of the ADD domain, and thus releases the autoinhibition of DNMT3A. The finding adds another layer of regulation of DNA methylation to ensure that the enzyme is mainly activated at proper targeting loci when unmethylated H3K4 is present, and strongly supports a negative correlation between H3K4me3 and DNA methylation across the mammalian genome. Our study provides a new insight into an unexpected autoinhibition and histone H3-induced activation of the de novo DNA methyltransferase after its initial genomic positioning.]]>
Thu, 29 Jan 2015 00:00:00 PST
Journal of cellular physiology: volume 230, number 5, may 2015.
J Cell Physiol (May 2015)

Cover: Protein binding partners of human Notch1 are visualized using the BioGRID website. Only physical interactions are shown and interspecies interactions are excluded. Canonical Notch binding partners are labeled in green, chromatin factors in red, and some examples of crosstalk to other signaling pathway mentioned in the text are labeled yellow. See reviews on Nuclear Receptors and Epigenomics in this issue: Schwanbeck, Wang et al., and Stachowiak et al. on pages 969-1002.]]>
Thu, 29 Jan 2015 00:00:00 PST
A Retrospective Likelihood Approach for Efficient Integration of Multiple Omics Factors in Case-Control Association Studies. Balliu B, Tsonaka R, Boehringer S, Houwing-Duistermaat J
Genet Epidemiol (Jan 2015)

Integrative omics, the joint analysis of outcome and multiple types of omics data, such as genomics, epigenomics, and transcriptomics data, constitute a promising approach for powerful and biologically relevant association studies. These studies often employ a case-control design, and often include nonomics covariates, such as age and gender, that may modify the underlying omics risk factors. An open question is how to best integrate multiple omics and nonomics information to maximize statistical power in case-control studies that ascertain individuals based on the phenotype. Recent work on integrative omics have used prospective approaches, modeling case-control status conditional on omics, and nonomics risk factors. Compared to univariate approaches, jointly analyzing multiple risk factors with a prospective approach increases power in nonascertained cohorts. However, these prospective approaches often lose power in case-control studies. In this article, we propose a novel statistical method for integrating multiple omics and nonomics factors in case-control association studies. Our method is based on a retrospective likelihood function that models the joint distribution of omics and nonomics factors conditional on case-control status. The new method provides accurate control of Type I error rate and has increased efficiency over prospective approaches in both simulated and real data.]]>
Mon, 26 Jan 2015 00:00:00 PST
Measuring epigenetics as the mediator of gene/environment interactions in DOHaD. Ong ML, Lin X, Holbrook JD
J Dev Orig Health Dis (Feb 2015)

Analysis of DNA methylation data in epigenome-wide association studies provides many bioinformatics and statistical challenges. Not least of these, are the non-independence of individual DNA methylation marks from each other, from genotype and from technical sources of variation. In this review we discuss DNA methylation data from the Infinium450K array and processing methodologies to reduce technical variation. We describe recent approaches to harness the concordance of neighbouring DNA methylation values to improve power in association studies. We also describe how the non-independence of genotype and DNA methylation has been used to infer causality (in the case of Mendelian randomization approaches); suggest the mediating effect of DNA methylation in linking intergenic single nucleotide polymorphisms, identified in genome-wide association studies, to phenotype; and to uncover the widespread influence of gene and environment interactions on methylation levels.]]>
Fri, 23 Jan 2015 00:00:00 PST
A systems-level approach to parental genomic imprinting: the imprinted gene network includes extracellular matrix genes and regulates cell cycle exit and differentiation. Al Adhami H, Evano B, Le Digarcher A, Gueydan C, Dubois E, Parrinello H, Dantec C, Bouschet T, Varrault A, Journot L
Genome Res (Jan 2015)

Genomic imprinting is an epigenetic mechanism that restrains the expression of ∼100 eutherian genes in a parent-of-origin-specific manner. The reason for this selective targeting of genes with seemingly disparate molecular functions is unclear. In the present work, we show that imprinted genes are coexpressed in a network that is regulated at the transition from proliferation to quiescence and differentiation during fibroblast cell cycle withdrawal, adipogenesis in vitro, and muscle regeneration in vivo. Imprinted gene regulation is not linked to alteration of DNA methylation or to perturbation of monoallelic, parent-of-origin-dependent expression. Overexpression and knockdown of imprinted gene expression alters the sensitivity of preadipocytes to contact inhibition and adipogenic differentiation. In silico and in cellulo experiments showed that the imprinted gene network includes biallelically expressed, nonimprinted genes. These control the extracellular matrix composition, cell adhesion, cell junction, and extracellular matrix-activated and growth factor-activated signaling. These observations show that imprinted genes share a common biological process that may account for their seemingly diverse roles in embryonic development, obesity, diabetes, muscle physiology, and neoplasm.]]>
Fri, 23 Jan 2015 00:00:00 PST
A new, improved and generalizable approach for the analysis of biological data generated by -omic platforms. Pleasants AB, Wake GC, Shorten PR, Hassell-Sweatman CZ, McLean CA, Holbrook JD, Gluckman PD, Sheppard AM
J Dev Orig Health Dis (Feb 2015)

The principles embodied by the Developmental Origins of Health and Disease (DOHaD) view of 'life history' trajectory are increasingly underpinned by biological data arising from molecular-based epigenomic and transcriptomic studies. Although a number of 'omic' platforms are now routinely and widely used in biology and medicine, data generation is frequently confounded by a frequency distribution in the measurement error (an inherent feature of the chemistry and physics of the measurement process), which adversely affect the accuracy of estimation and thus, the inference of relationships to other biological measures such as phenotype. Based on empirical derived data, we have previously derived a probability density function to capture such errors and thus improve the confidence of estimation and inference based on such data. Here we use published open source data sets to calculate parameter values relevant to the most widely used epigenomic and transcriptomic technologies Then by using our own data sets, we illustrate the benefits of this approach by specific application, to measurement of DNA methylation in this instance, in cases where levels of methylation at specific genomic sites represents either (1) a response variable or (2) an independent variable. Further, we extend this formulation to consideration of the 'bivariate' case, in which the co-dependency of methylation levels at two distinct genomic sites is tested for biological significance. These tools not only allow greater accuracy of measurement and improved confidence of functional inference, but in the case of epigenomic data at least, also reveal otherwise cryptic information.]]>
Fri, 23 Jan 2015 00:00:00 PST
The potential for epigenetic analysis of paediatric CNS tumours to improve diagnosis, treatment and prognosis. Sexton-Oates A, MacGregor D, Dodgshun A, Saffery R
Ann Oncol (Jan 2015)

Tumours of CNS origin are the second most prevalent group of cancers in children, yet account for the majority of childhood cancer-related deaths. Such tumours show diverse location, cell type of origin, disease course and long term outcome, both across and within tumour types, making treatment problematic and contributing to the relatively modest progress in reducing mortality over recent decades. As technological advances begin to reveal the genetic landscape of all cancers, it is becoming increasingly clear that genetic disruption represents only one 'layer' of molecular disruption associated with disease aetiology. Obtaining a full understanding of tumour behaviour requires an understanding of the cellular and molecular pathways disrupted during tumourigenesis, particularly in relation to gene expression. The utility of such an approach has allowed stratification of cancers such as medulloblastoma into subgroups based on molecular features, with potential to refine risk prediction. Given that epigenetic disruption is a universal feature of all human cancers, it is logical to speculate that interrogating epigenetic marks may help to further define the molecular profile, and therefore the clinical trajectory, of tumours. An integrated approach to build a molecular 'signature' of individual tumours that incorporates traditional morphological and demographic information, genetic and transcriptome analysis, in addition to epigenomics (DNA methylation and non-coding RNA analysis), offers tremendous promise to (i) inform treatment approach, (ii) facilitate accurate early identification (preferably at diagnosis) of variable risk groups (both good and poor prognosis groups), and (iii) track disease progression in childhood CNS tumours.]]>
Wed, 21 Jan 2015 00:00:00 PST
Genomics and epigenomics in novel schizophrenia drug discovery: translating animal models to clinical research and back. Bosia M, Pigoni A, Cavallaro R
Expert Opin Drug Discov (Feb 2015)

Schizophrenia is a major psychiatric disorder that afflicts about 1% of the world's population, falling into the top 10 medical disorders causing disability. Existing therapeutic strategies have had limited success; they have poor effects on core cognitive impairment and long-term disability. They are also burdened by relevant side effects. Although new antipsychotic medications have been launched in the past decades, there has been a general lack of significant innovation over the past 60 years. This lack of significant progress in the pharmacotherapy of schizophrenia is a reflection of the complexity and heterogeneity of its etiopathogenetic mechanisms.]]>
Tue, 20 Jan 2015 00:00:00 PST
The role and interaction of imprinted genes in human fetal growth. Moore GE, Ishida M, Demetriou C, Al-Olabi L, Leon LJ, Thomas AC, Abu-Amero S, Frost JM, Stafford JL, Chaoqun Y, Duncan AJ, Baigel R, Brimioulle M, Iglesias-Platas I, Apostolidou S, Aggarwal R, Whittaker JC, Syngelaki A, Nicolaides KH, Regan L, Monk D, Stanier P
Philos Trans R Soc Lond B Biol Sci (Mar 2015)

Identifying the genetic input for fetal growth will help to understand common, serious complications of pregnancy such as fetal growth restriction. Genomic imprinting is an epigenetic process that silences one parental allele, resulting in monoallelic expression. Imprinted genes are important in mammalian fetal growth and development. Evidence has emerged showing that genes that are paternally expressed promote fetal growth, whereas maternally expressed genes suppress growth. We have assessed whether the expression levels of key imprinted genes correlate with fetal growth parameters during pregnancy, either early in gestation, using chorionic villus samples (CVS), or in term placenta. We have found that the expression of paternally expressing insulin-like growth factor 2 (IGF2), its receptor IGF2R, and the IGF2/IGF1R ratio in CVS tissues significantly correlate with crown-rump length and birthweight, whereas term placenta expression shows no correlation. For the maternally expressing pleckstrin homology-like domain family A, member 2 (PHLDA2), there is no correlation early in pregnancy in CVS but a highly significant negative relationship in term placenta. Analysis of the control of imprinted expression of PHLDA2 gave rise to a maternally and compounded grand-maternally controlled genetic effect with a birthweight increase of 93/155 g, respectively, when one copy of the PHLDA2 promoter variant is inherited. Expression of the growth factor receptor-bound protein 10 (GRB10) in term placenta is significantly negatively correlated with head circumference. Analysis of the paternally expressing delta-like 1 homologue (DLK1) shows that the paternal transmission of type 1 diabetes protective G allele of rs941576 single nucleotide polymorphism (SNP) results in significantly reduced birth weight (-132 g). In conclusion, we have found that the expression of key imprinted genes show a strong correlation with fetal growth and that for both genetic and genomics data analyses, it is important not to overlook parent-of-origin effects.]]>
Tue, 20 Jan 2015 00:00:00 PST
Computational schemes for the prediction and annotation of enhancers from epigenomic assays. Whitaker JW, Nguyen TT, Zhu Y, Wildberg A, Wang W
Methods (Jan 2015)

Identifying and annotating distal regulatory enhancers is critical to understand the mechanisms that control gene expression and cell-type-specific activities. Next-generation sequencing techniques have provided us an exciting toolkit of genome-wide assays that can be used to predict and annotate enhancers. However, each assay comes with its own specific set of analytical needs if enhancer prediction is to be optimal. Furthermore, integration of multiple genome-wide assays allows for different genomic features to be combined, and can improve predictive performance. Herein, we review the genome-wide assays and analysis schemes that are used to predict and annotate enhancers. In particular, we focus on three key computational topics: predicting enhancer locations, determining the cell-type-specific activity of enhancers, and linking enhancers to their target genes.]]>
Mon, 19 Jan 2015 00:00:00 PST
Plasma methylated septin 9: a colorectal cancer screening marker. Molnár B, Tóth K, Barták BK, Tulassay Z
Expert Rev Mol Diagn (Feb 2015)

Colorectal cancer (CRC) is a slow-developing cancer (10-15 years) with one of the highest frequencies in the world's population. Many countries have implemented various CRC screening programs, but have not achieved the desired compliance. Colonoscopy - considered the gold standard for CRC screening - has its limitations as well as the other techniques used, such as irrigoscopy, sigmoidoscopy, fecal blood and hemoglobin tests. The biomarker septin 9 has been found to be hypermethylated in nearly 100% of tissue neoplasia specimens and detected in circulating DNA fractions of CRC patients. A commercially available assay for septin 9 has been developed with moderate sensitivity (∼70%) and specificity (∼90%) and a second generation assay, Epi proColon 2.0 (Epigenomics AG), shows increased sensitivity (∼92%). The performance of the assay proved to be independent of tumor site and reaches a high sensitivity of 77%, even in early cancer stages (I and II). Furthermore, septin 9 was recently used in follow-up studies for detection of early recurrence of CRC. This article evaluates the opportunities, known limitations and future perspectives of the recently introduced Epi proColon(®) 2.0 test, which is based on the detection of aberrantly methylated DNA of the v2 region of the septin 9 gene in plasma.]]>
Mon, 19 Jan 2015 00:00:00 PST
Single molecule and single cell epigenomics. Hyun BR, McElwee JL, Soloway PD
Methods (Jan 2015)

Dynamically regulated changes in chromatin states are vital for normal development and can produce disease when they go awry. Accordingly, much effort has been devoted to characterizing these states under normal and pathological conditions. Chromatin immunoprecipitation followed by sequencing (ChIP-seq) is the most widely used method to characterize where in the genome transcription factors, modified histones, modified nucleotides and chromatin binding proteins are found; bisulfite sequencing (BS-seq) and its variants are commonly used to characterize the locations of DNA modifications. Though very powerful, these methods are not without limitations. Notably, they are best at characterizing one chromatin feature at a time, yet chromatin features arise and function in combination. Investigators commonly superimpose separate ChIP-seq or BS-seq datasets, and then infer where chromatin features are found together. While these inferences might be correct, they can be misleading when the chromatin source has distinct cell types, or when a given cell type exhibits any cell to cell variation in chromatin state. These ambiguities can be eliminated by robust methods that directly characterize the existence and genomic locations of combinations of chromatin features in very small inputs of cells or ideally, single cells. Here we review single molecule epigenomic methods under development to overcome these limitations, the technical challenges associated with single molecule methods and their potential application to single cells.]]>
Mon, 19 Jan 2015 00:00:00 PST
Epigenetics and cardiovascular disease. Delbridge LM, Mellor KM, Wold LE
Life Sci (Jan 2015)

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Mon, 19 Jan 2015 00:00:00 PST
Combining MeDIP-seq and MRE-seq to investigate genome-wide CpG methylation. Li D, Zhang B, Xing X, Wang T
Methods (Jan 2015)

DNA CpG methylation is a widespread epigenetic mark in high eukaryotes including mammals. DNA methylation plays key roles in diverse biological processes such as X chromosome inactivation, transposable element repression, genomic imprinting, and control of gene expression. Recent advancements in sequencing-based DNA methylation profiling methods provide an unprecedented opportunity to measure DNA methylation in a genome-wide fashion, making it possible to comprehensively investigate the role of DNA methylation. Several methods have been developed, such as Whole Genome Bisulfite Sequencing (WGBS), Reduced Representation Bisulfite Sequencing (RRBS), and enrichment-based methods including Methylation Dependent ImmunoPrecipitation followed by sequencing (MeDIP-seq), methyl-CpG binding domain (MBD) protein-enriched genome sequencing (MBD-seq), methyltransferase-directed Transfer of Activated Groups followed by sequencing (mTAG), and Methylation-sensitive Restriction Enzyme digestion followed by sequencing (MRE-seq). These methods differ by their genomic CpG coverage, resolution, quantitative accuracy, cost, and software for analyzing the data. Among these, WGBS is considered the gold standard. However, it is still a cost-prohibitive technology for a typical laboratory due to the required sequencing depth. We found that by integrating two enrichment-based methods that are complementary in nature (i.e., MeDIP-seq and MRE-seq), we can significantly increase the efficiency of whole DNA methylome profiling. By using two recently developed computational algorithms (i.e., M&M and methylCRF), the combination of MeDIP-seq and MRE-seq produces genome-wide CpG methylation measurement at high coverage and high resolution, and robust predictions of differentially methylated regions. Thus, the combination of the two enrichment-based methods provides a cost-effective alternative to WGBS. In this article we describe both the experimental protocols for performing MeDIP-seq and MRE-seq, and the computational protocols for running M&M and methylCRF.]]>
Mon, 19 Jan 2015 00:00:00 PST
Molecular Regulation of Cardiomyocyte Differentiation. Paige SL, Plonowska K, Xu A, Wu SM
Circ Res (Jan 2015)

The heart is the first organ to form during embryonic development. Given the complex nature of cardiac differentiation and morphogenesis, it is not surprising that some form of congenital heart disease is present in ≈1 percent of newborns. The molecular determinants of heart development have received much attention over the past several decades. This has been driven in large part by an interest in understanding the causes of congenital heart disease coupled with the potential of using knowledge from developmental biology to generate functional cells and tissues that could be used for regenerative medicine purposes. In this review, we highlight the critical signaling pathways and transcription factor networks that regulate cardiomyocyte lineage specification in both in vivo and in vitro models. Special focus will be given to epigenetic regulators that drive the commitment of cardiomyogenic cells from nascent mesoderm and their differentiation into chamber-specific myocytes, as well as regulation of myocardial trabeculation.]]>
Fri, 16 Jan 2015 00:00:00 PST
Database resources of the National Center for Biotechnology Information.  
Nucleic Acids Res (Jan 2015)

The National Center for Biotechnology Information (NCBI) provides a large suite of online resources for biological information and data, including the GenBank(®) nucleic acid sequence database and the PubMed database of citations and abstracts for published life science journals. Additional NCBI resources focus on literature (Bookshelf, PubMed Central (PMC) and PubReader); medical genetics (ClinVar, dbMHC, the Genetic Testing Registry, HIV-1/Human Protein Interaction Database and MedGen); genes and genomics (BioProject, BioSample, dbSNP, dbVar, Epigenomics, Gene, Gene Expression Omnibus (GEO), Genome, HomoloGene, the Map Viewer, Nucleotide, PopSet, Probe, RefSeq, Sequence Read Archive, the Taxonomy Browser, Trace Archive and UniGene); and proteins and chemicals (Biosystems, COBALT, the Conserved Domain Database (CDD), the Conserved Domain Architecture Retrieval Tool (CDART), the Molecular Modeling Database (MMDB), Protein Clusters, Protein and the PubChem suite of small molecule databases). The Entrez system provides search and retrieval operations for many of these databases. Augmenting many of the Web applications are custom implementations of the BLAST program optimized to search specialized data sets. All of these resources can be accessed through the NCBI home page at http://www.ncbi.nlm.nih.gov.]]>
Fri, 16 Jan 2015 00:00:00 PST
Correction for Haig, Genomic imprinting and the evolutionary psychology of human kinship.
Proc Natl Acad Sci U S A (Jan 2015)

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Wed, 14 Jan 2015 00:00:00 PST
Pyrosequencing for Accurate Imprinted Allele Expression Analysis. Yang B, Damaschke N, Yao T, McCormick J, Wagner J, Jarrard D
J Cell Biochem (Jan 2015)

Genomic imprinting is an epigenetic mechanism that restricts gene expression to one inherited allele. Improper maintenance of imprinting has been implicated in a number of human diseases and developmental syndromes. Assays are needed that can quantify the contribution of each paternal allele to a gene expression profile. We have developed a rapid, sensitive quantitative assay for the measurement of individual allelic ratios termed Pyrosequencing for Imprinted Expression (PIE). Advantages of PIE over other approaches include shorter experimental time, decreased labor, avoiding the need for restriction endonuclease enzymes at polymorphic sites, and prevent heteroduplex formation which is problematic in quantitative PCR-based methods. We demonstrate the improved sensitivity of PIE including the ability to detect differences in allelic expression down to 1%. The assay is capable of measuring genomic heterozygosity as well as imprinting in a single run. PIE is applied to determine the status of Insulin-like Growth Factor-2 (IGF2) imprinting in human and mouse tissues. This article is protected by copyright. All rights reserved.]]>
Mon, 12 Jan 2015 00:00:00 PST
BioVLAB-MMIA-NGS: microRNA-mRNA integrated analysis using high-throughput sequencing data. Chae H, Rhee S, Nephew KP, Kim S
Bioinformatics (Jan 2015)

It is now well established that microRNAs (miRNAs) play a critical role in regulating gene expression in a sequence-specific manner, and genome-wide efforts are underway to predict known and novel miRNA targets. However, the integrated miRNA-mRNA analysis remains a major computational challenge, requiring powerful informatics systems and bioinformatics expertise.]]>
Sat, 10 Jan 2015 00:00:00 PST
Epigenetic Profile of Human Adventitial Progenitor Cells Correlates With Therapeutic Outcomes in a Mouse Model of Limb Ischemia. Gubernator M, Slater SC, Spencer HL, Spiteri I, Sottoriva A, Riu F, Rowlinson J, Avolio E, Katare R, Mangialardi G, Oikawa A, Reni C, Campagnolo P, Spinetti G, Touloumis A, Tavaré S, Prandi F, Pesce M, Hofner M, Klemens V, Emanueli C, Angelini G, Madeddu P
Arterioscler Thromb Vasc Biol (Jan 2015)

We investigated the association between the functional, epigenetic, and expressional profile of human adventitial progenitor cells (APCs) and therapeutic activity in a model of limb ischemia.]]>
Fri, 09 Jan 2015 00:00:00 PST