'; ?> 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 Mon, 20 Oct 2014 21:01:29 PDT Mon, 20 Oct 2014 21:01:29 PDT jirtle@radonc.duke.edu james001@jirtle.com Highly sensitive targeted methylome sequencing by post-bisulfite adaptor tagging. Miura F, Ito T
DNA Res (Oct 2014)

The current gold standard method for methylome analysis is whole-genome bisulfite sequencing (WGBS), but its cost is substantial, especially for the purpose of multi-sample comparison of large methylomes. Shotgun bisulfite sequencing of target-enriched DNA, or targeted methylome sequencing (TMS), can be a flexible, cost-effective alternative to WGBS. However, the current TMS protocol requires a considerable amount of input DNA and hence is hardly applicable to samples of limited quantity. Here we report a method to overcome this limitation by using post-bisulfite adaptor tagging (PBAT), in which adaptor tagging is conducted after bisulfite treatment to circumvent bisulfite-induced loss of intact sequencing templates, thereby enabling TMS of a 100-fold smaller amount of input DNA with far fewer cycles of polymerase chain reaction than in the current protocol. We thus expect that the PBAT-mediated TMS will serve as an invaluable method in epigenomics.]]>
Fri, 17 Oct 2014 00:00:00 PDT
Single-nucleotide polymorphisms and DNA methylation markers associated with central obesity and regulation of body weight. Goni L, Milagro FI, Cuervo M, Martínez JA
Nutr Rev (Oct 2014)

Visceral fat is strongly associated with the development of specific obesity-related metabolic alterations. Genetic and epigenetic mechanisms seem to be involved in the development of obesity and visceral adiposity. The aims of this review are to identify the single-nucleotide polymorphisms related to central obesity and to summarize the main findings on DNA methylation and obesity. A search of the MEDLINE database was conducted to identify genome-wide association studies, meta-analyses of genome-wide association studies, and gene-diet interaction studies related to central obesity, and, in addition, studies that analyzed DNA methylation in relation to body weight regulation. A total of 8 genome-wide association studies and 9 meta-analyses of genome-wide association studies reported numerous single-nucleotide polymorphisms to be associated with central obesity. Ten studies analyzed gene-diet interactions and central obesity, while 2 epigenome-wide association studies analyzed DNA methylation patterns and obesity. Nine studies investigated the relationship between DNA methylation and weight loss, excess body weight, or adiposity outcomes. Given the development of new sequencing and omics technologies, significantly more knowledge on genomics and epigenomics of obesity and body fat distribution will emerge in the near future.]]>
Fri, 17 Oct 2014 00:00:00 PDT
Epigenomics of macrophages. Gosselin D, Glass CK
Immunol Rev (Nov 2014)

Macrophages play essential roles in tissue homeostasis, pathogen elimination, and tissue repair. A defining characteristic of these cells is their ability to efficiently adapt to a variety of abruptly changing and complex environments. This ability is intrinsically linked to a capacity to quickly alter their transcriptome, and this is tightly associated with the epigenomic organization of these cells and, in particular, their enhancer repertoire. Indeed, enhancers are genomic sites that serve as platforms for the integration of signaling pathways with the mechanisms that regulate mRNA transcription. Notably, transcription is pervasive at active enhancers and enhancer RNAs (eRNAs) are tightly coupled to regulated transcription of protein-coding genes. Furthermore, given that each cell type possesses a defining enhancer repertoire, studies on enhancers provide a powerful method to study how specialization of functions among the diverse macrophage subtypes may arise. Here, we review recent studies providing insights into the distinct mechanisms that contribute to the establishment of enhancers and their role in the regulation of transcription in macrophages.]]>
Thu, 16 Oct 2014 00:00:00 PDT
Altered gene expression in human placentas after IVF/ICSI. Nelissen EC, Dumoulin JC, Busato F, Ponger L, Eijssen LM, Evers JL, Tost J, van Montfoort AP
Hum Reprod (Oct 2014)

Is gene expression in placental tissue of IVF/ICSI patients altered when compared with a spontaneously conceived group, and are these alterations due to loss of imprinting (LOI) in the case of imprinted genes?]]>
Wed, 15 Oct 2014 00:00:00 PDT
Imprinting analysis of the mouse chromosome 7C region in DNMT1-null embryos. Nakagaki A, Osanai H, Kishino T
Gene (Oct 2014)

The mouse chromosome 7C, orthologous to the human 15q11-q13 has an imprinted domain, where most of the genes are expressed only from the paternal allele. The imprinted domain contains paternally expressed genes, Snurf/Snrpn, Ndn, Magel2, Mkrn3, and Frat3, C/D-box small nucleolar RNAs (snoRNAs), and the maternally expressed gene, Ube3a. Imprinted expression in this large (approximately 3-4Mb) domain is coordinated by a bipartite cis-acting imprinting center (IC), located upstream of the Snurf/Snrpn gene. The molecular mechanism how IC regulates gene expression of the whole domain remains partially understood. Here we analyzed the relationship between imprinted gene expression and DNA methylation in the mouse chromosome 7C using DNA methyltransferase 1 (DNMT1)-null mutant embryos carrying Dnmt1(ps) alleles, which show global loss of DNA methylation and embryonic lethality. In the DNMT1-null embryos at embryonic day 9.5, the paternally expressed genes were biallelically expressed. Bisulfite DNA methylation analysis revealed loss of methylation on the maternal allele in the promoter regions of the genes. These results demonstrate that DNMT1 is necessary for monoallelic expression of the imprinted genes in the chromosome 7C domain, suggesting that DNA methylation in the secondary differentially methylated regions (DMRs), which are acquired during development serves primarily to control the imprinted expression from the maternal allele in the mouse chromosome 7C.]]>
Tue, 14 Oct 2014 00:00:00 PDT
Current trend of annotating single nucleotide variation in humans - a case study on SNVrap. Li MJ, Wang J
Methods (Oct 2014)

As high throughput methods, such as whole genome genotyping arrays, whole exome sequencing (WES) and whole genome sequencing (WGS), have detected huge amounts of genetic variants associated with human diseases, function annotation of these variants is an indispensable step in understanding disease etiology. Large-scale functional genomics projects, such as The ENCODE Project and Roadmap Epigenomics Project, provide genome-wide profiling of functional elements across different human cell types and tissues. With the urgent demands for identification of disease-causal variants, comprehensive and easy-to-use annotation tool is highly in demand. Here we review and discuss current progress and trend of the variant annotation field. Furthermore, we introduce a comprehensive web portal for annotating human genetic variants. We use gene-based features and the latest functional genomics datasets to annotate single nucleotide variation (SNVs) in human, at whole genome scale. We further apply several function prediction algorithms to annotate SNVs that might affect different biological processes, including transcriptional gene regulation, alternative splicing, post-transcriptional regulation, translation and post-translational modifications. The SNVrap web portal is freely available at http://jjwanglab.org/snvrap.]]>
Mon, 13 Oct 2014 00:00:00 PDT
Analysis of methylation microarray for tissue specific detection. Muangsub T, Samsuwan J, Tongyoo P, Kitkumthorn N, Mutirangura A
Gene (Oct 2014)

The role of human DNA methylation has been extensively studied in genomic imprinting, X-inactivation, and disease. However, studies of tissue-specific methylation remain limited. In this study, we use bioinformatics methods to analyze methylation data and reveal loci that are exclusively methylated or unmethylated in individual tissues. We collect 39 previously published DNA methylation profiles using an Illumina® HumanMethylation 27 BeadChip Kit containing 22 common tissues and involving 27,578 CpG loci across the human genome. We found 86 positions of tissue specific methylation CpG (TSM) that encompass 34 hypermethylated TSMs (31 genes) and 52 hypomethylated TSMs (47 genes). Tissues were found to contain 1 to 25 TSM loci, with the majority in the liver (25), testis (18), and brain (16). Fewer TSM loci were found in the muscle (8), ovary (7), adrenal gland (3), pancreas (2-4), kidney, spleen, and stomach (1 each). TSMs are predominantly located 0-300 base pairs in the 3' direction after the transcription start site. Similar to known promoters of methylation, hypermethylated TSM genes suppress transcription, while hypomethylated TSMs allow gene transcription. The majority of hypermethylated TSM genes encode membrane proteins and receptors, while hypomethylated TSM genes primarily encode signal peptides and tissue-specific proteins. In summary, the database of TSM loci produced herein is useful for the selection of tissue-specific DNA markers as diagnostic tools, as well as for the further study of the mechanisms and roles of TSM.]]>
Sat, 11 Oct 2014 00:00:00 PDT
Cooperativity, specificity, and evolutionary stability of polycomb targeting in Drosophila. Schuettengruber B, Oded Elkayam N, Sexton T, Entrevan M, Stern S, Thomas A, Yaffe E, Parrinello H, Tanay A, Cavalli G
Cell Rep (Oct 2014)

Metazoan genomes are partitioned into modular chromosomal domains containing active or repressive chromatin. In flies, Polycomb group (PcG) response elements (PREs) recruit PHO and other DNA-binding factors and act as nucleation sites for the formation of Polycomb repressive domains. The sequence specificity of PREs is not well understood. Here, we use comparative epigenomics and transgenic assays to show that Drosophila domain organization and PRE specification are evolutionarily conserved despite significant cis-element divergence within Polycomb domains, whereas cis-element evolution is strongly correlated with transcription factor binding divergence outside of Polycomb domains. Cooperative interactions of PcG complexes and their recruiting factor PHO stabilize PHO recruitment to low-specificity sequences. Consistently, PHO recruitment to sites within Polycomb domains is stabilized by PRC1. These data suggest that cooperative rather than hierarchical interactions among low-affinity sequences, DNA-binding factors, and the Polycomb machinery are giving rise to specific and strongly conserved 3D structures in Drosophila.]]>
Sat, 11 Oct 2014 00:00:00 PDT
Phytoestrogens and prevention of breast cancer: The contentious debate. Bilal I, Chowdhury A, Davidson J, Whitehead S
World J Clin Oncol (Oct 2014)

Phytoestrogens have multiple actions within target cells, including the epigenome, which could be beneficial to the development and progression of breast cancer. In this brief review the action of phytoestrogens on oestrogen receptors, cell signalling pathways, regulation of the cell cycle, apoptosis, steroid synthesis and epigenetic events in relation to breast cancer are discussed. Phytoestrogens can bind weakly to oestrogen receptors (ERs) and some have a preferential affinity for ERβ which can inhibit the transcriptional growth-promoting activity of ERα. However only saturating doses of phytoestrogens, stimulating both ERα and β, exert growth inhibitory effects. Such effects on growth may be through phytoestrogens inhibiting cell signalling pathways. Phytoestrogens have also been shown to inhibit cyclin D1 expression but increase the expression of cyclin-dependent kinase inhibitors (p21 and p27) and the tumour suppressor gene p53. Again these effects are only observed at high (> 10) µmol/L doses of phytoestrogens. Finally the effects of phytoestrogens on breast cancer may be mediated by their ability to inhibit local oestrogen synthesis and induce epigenetic changes. There are, though, difficulties in reconciling epidemiological and experimental data due to the fact experimental doses, both in vivo and in vitro, far exceed the circulating concentrations of "free" unbound phytoestrogens measured in women on a high phytoestrogen diet or those taking phytoestrogen supplements.]]>
Fri, 10 Oct 2014 00:00:00 PDT
The Role of CCCTC-Binding Factor (CTCF) in Genomic Imprinting, Development, and Reproduction. Franco MM, Prickett AR, Oakey RJ
Biol Reprod (Oct 2014)

CCCTC-binding factor (CTCF) is the major protein involved in insulator activity in vertebrates, with widespread DNA binding sites in the genome. CTCF participates in many processes related to global chromatin organization and remodeling, contributing to the repression or activation of gene transcription. It is also involved in epigenetic reprogramming and is essential during gametogenesis and embryo development. Abnormal DNA methylation patterns at CTCF motifs may impair CTCF binding to DNA and are related to fertility disorders in mammals. Therefore, CTCF and its binding sites are important candidate regions to be investigated as molecular markers for gamete and embryo quality. This article reviews the role of CTCF in genomic imprinting, gametogenesis and early embryo development and moreover, highlights potential opportunities for environmental influences associated with assisted reproductive techniques (ARTs) to affect CTCF mediated processes. We discuss the potential use of CTCF as a molecular marker for assessing gamete and embryo quality in the context of improving the efficiency and safety of ARTs.]]>
Thu, 09 Oct 2014 00:00:00 PDT
Haploid mouse embryonic stem cells: rapid genetic screening and germline transmission. Wutz A
Annu Rev Cell Dev Biol (Oct 2014)

Most animal genomes are diploid, and mammalian development depends on specific adaptations that have evolved secondary to diploidy. Genomic imprinting and dosage compensation restrict haploid development to early embryos. Recently, haploid mammalian development has been reinvestigated since the establishment of haploid embryonic stem cells (ESCs) from mouse embryos. Haploid cells possess one copy of each gene, facilitating the generation of loss-of-function mutations in a single step. Recessive mutations can then be assessed in forward genetic screens. Applications of haploid mammalian cell systems in screens have been illustrated in several recent publications. Haploid ESCs are characterized by a wide developmental potential and can contribute to chimeric embryos and mice. Different strategies for introducing genetic modifications from haploid ESCs into the mouse germline have been further developed. Haploid ESCs therefore introduce new possibilities in mammalian genetics and could offer an unprecedented tool for genome exploration in the future.]]>
Tue, 07 Oct 2014 00:00:00 PDT
Twists and turns: a scientific journey. Tilghman SM
Annu Rev Cell Dev Biol (Oct 2014)

In this perspective I look back on the twists and turns that influenced the direction of my scientific career over the past 40 years. From my early ambition to be a chemist to my training in Philadelphia and Bethesda as a molecular biologist, I benefited enormously from generous and valuable mentoring. In my independent career in Philadelphia and Princeton, I was motivated by a keen interest in the changes in gene expression that direct the development of the mammalian embryo and inspired by the creativity and energy of my students, fellows, and research staff. After twelve years as President of Princeton University, I have happily returned to the faculty of the Department of Molecular Biology.]]>
Tue, 07 Oct 2014 00:00:00 PDT
Epigenetics reloaded: the single-cell revolution. Bheda P, Schneider R
Trends Cell Biol (Oct 2014)

Mechanistically, how epigenetic states are inherited through cellular divisions remains an important open question in the chromatin field and beyond. Defining the heritability of epigenetic states and the underlying chromatin-based mechanisms within a population of cells is complicated due to cell heterogeneity combined with varying levels of stability of these states; thus, efforts must be focused toward single-cell analyses. The approaches presented here constitute the forefront of epigenetics research at the single-cell level using classic and innovative methods to dissect epigenetics mechanisms from the limited material available in a single cell. This review further outlines exciting future avenues of research to address the significance of epigenetic heterogeneity and the contributions of microfluidics technologies to single-cell isolation and analysis.]]>
Mon, 06 Oct 2014 00:00:00 PDT
Epigenetics and social context: implications for disparity in cardiovascular disease. Saban KL, Mathews HL, DeVon HA, Janusek LW
Aging Dis (Oct 2014)

Although it is well established that African Americans (AA) experience greater social stressors than non-Hispanic Whites (NHW), the extent to which early life adversity and cumulative social stressors such as perceived discrimination, neighborhood violence, subjective social status, and socioeconomic status contribute to disparity in coronary heart disease (CHD) and stroke between AA and NHW are not well understood.]]>
Fri, 03 Oct 2014 00:00:00 PDT
Genome-wide DNA methylation patterns in LSH mutant reveals de-repression of repeat elements and redundant epigenetic silencing pathways. Yu W, McIntosh C, Lister R, Zhu I, Han Y, Ren J, Landsman D, Lee E, Briones V, Terashima M, Leighty R, Ecker JR, Muegge K
Genome Res (Oct 2014)

Cytosine methylation is critical in mammalian development and plays a role in diverse biologic processes such as genomic imprinting, X chromosome inactivation, and silencing of repeat elements. Several factors regulate DNA methylation in early embryogenesis, but their precise role in the establishment of DNA methylation at a given site remains unclear. We have generated a comprehensive methylation map in fibroblasts derived from the murine DNA methylation mutant Hells(-/-) (helicase, lymphoid specific, also known as LSH). It has been previously shown that HELLS can influence de novo methylation of retroviral sequences and endogenous genes. Here, we describe that HELLS controls cytosine methylation in a nuclear compartment that is in part defined by lamin B1 attachment regions. Despite widespread loss of cytosine methylation at regulatory sequences, including promoter regions of protein-coding genes and noncoding RNA genes, overall relative transcript abundance levels in the absence of HELLS are similar to those in wild-type cells. A subset of promoter regions shows increases of the histone modification H3K27me3, suggesting redundancy of epigenetic silencing mechanisms. Furthermore, HELLS modulates CG methylation at all classes of repeat elements and is critical for repression of a subset of repeat elements. Overall, we provide a detailed analysis of gene expression changes in relation to DNA methylation alterations, which contributes to our understanding of the biological role of cytosine methylation.]]>
Thu, 02 Oct 2014 00:00:00 PDT
Long non-coding RNAs in glioma: Functional roles and clinical perspectives. Zhang XQ, Leung GK
Neurochem Int (Nov 2014)

Long non-coding RNAs (lncRNAs) are a new class of non-coding gene regulators. But unlike their smaller counterparts, microRNAs, relatively less is known about the roles and functions of lncRNAs. Current evidence suggests that lncRNAs may play important roles in a wide range of biological processes in human cancers, including glioma. By acting as oncogenes or tumor suppressors, lncRNAs may contribute to glioma initiation, progression and other malignant phenotypes. Their expression profiles may also have important clinical implications in glioma subclassification and patients' prognostication. Here, we review current evidence related to the functional roles of lncRNAs in glioma. We will discuss the aberrant lncRNA expression signatures associated with glioma initiation and progression, as well as the potential mechanisms underlying lncRNA dysregulation. We also discuss the functional roles of lncRNAs in glioma biological behavior. Finally, the potentials and prospects of employing lncRNAs as novel biomarkers and therapeutic targets for glioma clinical practice will also be addressed.]]>
Fri, 26 Sep 2014 00:00:00 PDT
Relevance of genomic imprinting in intrauterine human growth expression of CDKN1C, H19, IGF2, KCNQ1 and PHLDA2 imprinted genes. Cordeiro A, Neto AP, Carvalho F, Ramalho C, Dória S
J Assist Reprod Genet (Oct 2014)

To study the relationship of imprinted gene expression (CDKN1C, H19, IGF2, KCNQ1 and PHLDA2) with human fetal growth.]]>
Tue, 23 Sep 2014 00:00:00 PDT
Opposite risk patterns for autism and schizophrenia are associated with normal variation in birth size: phenotypic support for hypothesized diametric gene-dosage effects. Byars SG, Stearns SC, Boomsma JJ
Proc Biol Sci (Nov 2014)

Opposite phenotypic and behavioural traits associated with copy number variation and disruptions to imprinted genes with parent-of-origin effects have led to the hypothesis that autism and schizophrenia share molecular risk factors and pathogenic mechanisms, but a direct phenotypic comparison of how their risks covary has not been attempted. Here, we use health registry data collected on Denmark's roughly 5 million residents between 1978 and 2009 to detect opposing risks of autism and schizophrenia depending on normal variation (mean ± 1 s.d.) in adjusted birth size, which we use as a proxy for diametric gene-dosage variation in utero. Above-average-sized babies (weight, 3691-4090 g; length, 52.8-54.3 cm) had significantly higher risk for autism spectrum (AS) and significantly lower risk for schizophrenia spectrum (SS) disorders. By contrast, below-average-sized babies (2891-3290 g; 49.7-51.2 cm) had significantly lower risk for AS and significantly higher risk for SS disorders. This is the first study directly comparing autism and schizophrenia risks in the same population, and provides the first large-scale empirical support for the hypothesis that diametric gene-dosage effects contribute to these disorders. Only the kinship theory of genomic imprinting predicts the opposing risk patterns that we discovered, suggesting that molecular research on mental disease risk would benefit from considering evolutionary theory.]]>
Thu, 18 Sep 2014 00:00:00 PDT
Exploring breast carcinogenesis through integrative genomics and epigenomics analyses. Minning C, Mokhtar NM, Abdullah N, Muhammad R, Emran NA, Ali SA, Harun R, Jamal R
Int J Oncol (Nov 2014)

There have been many DNA methylation studies on breast cancer which showed various methylation patterns involving tumour suppressor genes and oncogenes but only a few of those studies link the methylation data with gene expression. More data are required especially from the Asian region and to analyse how the epigenome data correlate with the transcriptome. DNA methylation profiling was carried out on 76 fresh frozen primary breast tumour tissues and 25 adjacent non-cancerous breast tissues using the Illumina Infinium® HumanMethylation27 BeadChip. Validation of methylation results was performed on 7 genes using either MS-MLPA or MS-qPCR. Gene expression profiling was done on 15 breast tumours and 5 adjacent non-cancerous breast tissues using the Affymetrix GeneChip® Human Gene 1.0 ST array. The overlapping genes between DNA methylation and gene expression datasets were further mapped to the KEGG database to identify the molecular pathways that linked these genes together. Supervised hierarchical cluster analysis revealed 1,389 hypermethylated CpG sites and 22 hypomethylated CpG sites in cancer compared to the normal samples. Gene expression microarray analysis using a fold-change of at least 1.5 and a false discovery rate (FDR) at p>0.05 identified 404 upregulated and 463 downregulated genes in cancer samples. Integration of both datasets identified 51 genes with hypermethylation with low expression (negative association) and 13 genes with hypermethylation with high expression (positive association). Most of the overlapping genes belong to the focal adhesion and extracellular matrix-receptor interaction that play important roles in breast carcinogenesis. The present study displayed the value of using multiple datasets in the same set of tissues and how the integrative analysis can create a list of well-focused genes as well as to show the correlation between epigenetic changes and gene expression. These gene signatures can help us understand the epigenetic regulation of gene expression and could be potential targets for therapeutic intervention in the future.]]>
Mon, 15 Sep 2014 00:00:00 PDT
Genomic imprinting analysis of Igf2/H19 in porcine cloned fetuses using parthenogenetic somatic cells as nuclear donors. Wang D, Song Y, Huang Y, Duan F, Lv Q, Ouyang H, Lai L, Li Z
Biotechnol Lett (Oct 2014)

To gain insight into parthenogenesis in pigs, we report for the first time that using parthenogenetic somatic cells as nuclear donors (PSCNT), the porcine parthenogenetic fetus can develop to gestational day 39. Weight and morphological analysis revealed that PSCNT fetuses were smaller and developmentally retarded when compared to normally fertilized controls. Quantitative gene expression analysis indicated that in PSCNT fetuses, H19 was over-expressed, whereas Igf2 was significantly reduced (p < 0.05) compared with their controls. In addition, bisulfite-sequencing PCR results demonstrated that H19 differentially DNA methylated regions (DMRs) were hypomethylated in PSCNT fetuses, while Igf2 DMRs were hypermethylated in both PSCNT and control fetuses. Our results suggest that extended development of the porcine parthenogenetic fetus can be accomplished using PSCNT and that abnormal DNA methylation of H19 DMRs might contribute to the critical barrier of parthenogenesis in pigs.]]>
Tue, 02 Sep 2014 00:00:00 PDT