'; ?> 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, 28 Aug 2014 10:12:27 PDT Thu, 28 Aug 2014 10:12:27 PDT jirtle@radonc.duke.edu james001@jirtle.com The miR-379/miR-410 cluster at the imprinted Dlk1-Dio3 domain controls neonatal metabolic adaptation. Labialle S, Marty V, Bortolin-Cavaillé ML, Hoareau-Osman M, Pradère JP, Valet P, Martin PG, Cavaillé J
EMBO J (Aug 2014)

In mammals, birth entails complex metabolic adjustments essential for neonatal survival. Using a mouse knockout model, we identify crucial biological roles for the miR-379/miR-410 cluster within the imprinted Dlk1-Dio3 region during this metabolic transition. The miR-379/miR-410 locus, also named C14MC in humans, is the largest known placental mammal-specific miRNA cluster, whose 39 miRNA genes are expressed only from the maternal allele. We found that heterozygote pups with a maternal-but not paternal-deletion of the miRNA cluster display partially penetrant neonatal lethality with defects in the maintenance of energy homeostasis. This maladaptive metabolic response is caused, at least in part, by profound changes in the activation of the neonatal hepatic gene expression program, pointing to as yet unidentified regulatory pathways that govern this crucial metabolic transition in the newborn's liver. Not only does our study highlight the physiological importance of miRNA genes that recently evolved in placental mammal lineages but it also unveils additional layers of RNA-mediated gene regulation at the Dlk1-Dio3 domain that impose parent-of-origin effects on metabolic control at birth and have likely contributed to mammal evolution.]]>
Thu, 21 Aug 2014 00:00:00 PDT
Histone deacetylase 9 represses cholesterol efflux and alternatively activated macrophages in atherosclerosis development. Cao Q, Rong S, Repa JJ, Clair RS, Parks JS, Mishra N
Arterioscler Thromb Vasc Biol (Sep 2014)

Recent genome-wide association studies revealed that a genetic variant in the loci corresponding to histone deacetylase 9 (HDAC9) is associated with large vessel stroke. HDAC9 expression was upregulated in human atherosclerotic plaques in different arteries. The molecular mechanisms how HDAC9 might increase atherosclerosis is not clear.]]>
Thu, 21 Aug 2014 00:00:00 PDT
DNA modifications in the mammalian brain. Shin J, Ming GL, Song H
Philos Trans R Soc Lond B Biol Sci (Sep 2014)

DNA methylation is a crucial epigenetic mark in mammalian development, genomic imprinting, X-inactivation, chromosomal stability and suppressing parasitic DNA elements. DNA methylation in neurons has also been suggested to play important roles for mammalian neuronal functions, and learning and memory. In this review, we first summarize recent discoveries and fundamental principles of DNA modifications in the general epigenetics field. We then describe the profiles of different DNA modifications in the mammalian brain genome. Finally, we discuss roles of DNA modifications in mammalian brain development and function.]]>
Tue, 19 Aug 2014 00:00:00 PDT
Comparative epigenomics: defining and utilizing epigenomic variations across species, time-course, and individuals. Xiao S, Cao X, Zhong S
Wiley Interdiscip Rev Syst Biol Med (Sep 2014)

Epigenomic profiling, by revealing genome-wide distributions of epigenetic modifications, generated a large amount of structural information about the chromosomes. Epigenomic analysis has quickly become a big data science, posing tremendous challenges on its translation into knowledge. To meet this challenge, comparative analysis of epigenomes, dubbed comparative epigenomics, has emerged as an active research area. Here, we summarize the recent developments in comparative epigenomic analyses into three major directions, namely the comparisons across species, the time-course of a biological process, and individuals. We review the main ideas, methods, and findings in each direction, and discuss the implications to understanding the regulatory functions of the genomes. WIREs Syst Biol Med 2014, 6:345-352. doi: 10.1002/wsbm.1274 For further resources related to this article, please visit the WIREs website.]]>
Mon, 18 Aug 2014 00:00:00 PDT
DNA methyltransferase haplotype is associated with Alzheimer's disease. Pezzi JC, Ens CM, Borba EM, Schumacher-Schuh AF, de Andrade FM, Chaves ML, Fiegenbaum M, Camozzato AL
Neurosci Lett (Sep 2014)

Epigenetic mechanisms have been implicated in syndromes associated with neuropsychiatric disorders, but little is known about the role of epigenetics in Alzheimer's disease (AD). DNA methylation, one of the main epigenetic mechanisms, is a complex process carried out by specific enzymes, such as DNMT1 and DNMT3B. This study aimed to investigate the association between DNMT1 and DNMT3B polymorphisms and AD. Two hundred and ten elderly subjects (108 healthy controls and 102 with AD-NINCDS/ARDA, DSM-IV-TR criteria) were assessed. DNA was obtained from whole blood, and genotypes were detected by an allelic discrimination assay using TaqMan(®) MGB probes on a real-time PCR system. The polymorphisms studied were rs2162560, rs759920 (DNMT1) and rs998382, rs2424913, rs2424932 (DNMT3B). For both genes, the polymorphisms were in strong linkage disequilibrium. Carriers of the DNMT3B TGG haplotype were associated with AD (OR=3.03, 95% CI 1.63 to 5.63, P<0.001). No significant difference between AD and the control group were observed for DNMT1 polymorphisms. This study is one of the first describing a significant association between DNMT3B polymorphisms and AD. This enzyme, which is responsible for methylation in a general way, may be involved in AD.]]>
Mon, 18 Aug 2014 00:00:00 PDT
Genome-wide association identifies regulatory Loci associated with distinct local histogram emphysema patterns. Castaldi PJ, Cho MH, San José Estépar R, McDonald ML, Laird N, Beaty TH, Washko G, Crapo JD, Silverman EK,  
Am J Respir Crit Care Med (Aug 2014)

Emphysema is a heritable trait that occurs in smokers with and without chronic obstructive pulmonary disease. Emphysema occurs in distinct pathologic patterns, but the genetic determinants of these patterns are unknown.]]>
Sat, 16 Aug 2014 00:00:00 PDT
Human in vitro oocyte maturation is not associated with increased imprinting error rates at LIT1, SNRPN, PEG3 and GTL2. Kuhtz J, Romero S, De Vos M, Smitz J, Haaf T, Anckaert E
Hum Reprod (Sep 2014)

Does in vitro maturation (IVM) of cumulus-enclosed germinal vesicle (GV) stage oocytes retrieved from small antral follicles in minimally stimulated cycles without an ovulatory hCG dose induce imprinting errors at LIT1, SNRPN, PEG3 and GTL2 in human oocytes?]]>
Fri, 15 Aug 2014 00:00:00 PDT
Epigenetic upregulation of large-conductance Ca2+-activated k+ channel expression in uterine vascular adaptation to pregnancy. Chen M, Dasgupta C, Xiong F, Zhang L
Hypertension (Sep 2014)

Our previous study demonstrated that pregnancy increased large-conductance Ca(2+)-activated potassium channel β1 subunit (BKβ1) expression and large-conductance Ca(2+)-activated potassium channel activity in uterine arteries, which were abrogated by chronic hypoxia. The present study tested the hypothesis that promoter methylation/demethylation is a key mechanism in epigenetic reprogramming of BKβ1 expression patterns in uterine arteries. Ovine BKβ1 promoter of 2315 bp spanning from -2211 to +104 of the transcription start site was cloned, and an Sp1-380 binding site that contains CpG dinucleotide in its core binding sequences was identified. Site-directed deletion of the Sp1 site significantly decreased the BKβ1 promoter activity. Estrogen receptor-α bound to the Sp1 site through tethering to Sp1 and upregulated the expression of BKβ1. The Sp1 binding site at BKβ1 promoter was highly methylated in uterine arteries of nonpregnant sheep, and methylation inhibited transcription factor binding and BKβ1 promoter activity. Pregnancy caused a significant decrease in CpG methylation at the Sp1 binding site and increased Sp1 binding to the BKβ1 promoter and BKβ1 mRNA abundance. Chronic hypoxia during gestation abrogated this pregnancy-induced demethylation and upregulation of BKβ1 expression. The results provide evidence of a novel mechanism of promoter demethylation in pregnancy-induced reprogramming of large-conductance Ca(2+)-activated potassium channel expression and function in uterine arteries and suggest new insights of epigenetic mechanisms linking gestational hypoxia to aberrant uteroplacental circulation and increased risk of preeclampsia.]]>
Fri, 15 Aug 2014 00:00:00 PDT
[Influence of assisted reproduction technologies on genomic imprinting of embryos and offspring]. Hu C, Wang L, Le F, Jin F
Zhonghua Yi Xue Yi Chuan Xue Za Zhi (Aug 2014)

Assisted reproduction technologies (ART) include controlled ovarian hyperstimulation, in vitro fertilization-embryo transfer, intracytoplasmic sperm injection, in vitro maturation of oocytes, pre-implantation genetic diagnosis, etc. They have been used for the treatment of impaired fertility but may damage the health of offspring. The ART procedures may alter the epigenetic status of these offspring and DNA methylation may be a crucial mechanism. This paper summarizes epigenetic alterations in ART embryos and offspring, and discusses the risks.]]>
Thu, 14 Aug 2014 00:00:00 PDT
Personalized nutrition and obesity. Qi L
Ann Med (Aug 2014)

Abstract The past few decades have witnessed a rapid rise in nutrition-related disorders such as obesity in the United States and over the world. Traditional nutrition research has associated various foods and nutrients with obesity. Recent advances in genomics have led to identification of the genetic variants determining body weight and related dietary factors such as intakes of energy and macronutrients. In addition, compelling evidence has lent support to interactions between genetic variations and dietary factors in relation to obesity and weight change. Moreover, recently emerging data from other 'omics' studies such as epigenomics and metabolomics suggest that more complex interplays between the global features of human body and dietary factors may exist at multiple tiers in affecting individuals' susceptibility to obesity; and a concept of 'personalized nutrition' has been proposed to integrate this novel knowledge with traditional nutrition research, with the hope ultimately to endorse person-centric diet intervention to mitigate obesity and related disorders.]]>
Mon, 04 Aug 2014 00:00:00 PDT
Reactivation of maternal SNORD116 cluster via SETDB1 knockdown in Prader-Willi syndrome iPSCs. Cruvinel E, Budinetz T, Germain N, Chamberlain S, Lalande M, Martins-Taylor K
Hum Mol Genet (Sep 2014)

Prader-Willi syndrome (PWS), a disorder of genomic imprinting, is characterized by neonatal hypotonia, hypogonadism, small hands and feet, hyperphagia and obesity in adulthood. PWS results from the loss of paternal copies of the cluster of SNORD116 C/D box snoRNAs and their host transcript, 116HG, on human chromosome 15q11-q13. We have investigated the mechanism of repression of the maternal SNORD116 cluster and 116HG. Here, we report that the zinc-finger protein ZNF274, in association with the histone H3 lysine 9 (H3K9) methyltransferase SETDB1, is part of a complex that binds to the silent maternal but not the active paternal alleles. Knockdown of SETDB1 in PWS-specific induced pluripotent cells (iPSCs) causes a decrease in the accumulation of H3K9 trimethylation (H3K9me3) at 116HG and corresponding accumulation of the active chromatin mark histone H3 lysine 4 dimethylation (H3K4me2). We also show that upon knockdown of SETDB1 in PWS-specific iPSCs, expression of maternally silenced 116HG RNA is partially restored. SETDB1 knockdown in PWS iPSCs also disrupts DNA methylation at the PWS-IC where a decrease in 5-methylcytosine is observed in association with a concomitant increase in 5-hydroxymethylcytosine. This observation suggests that the ZNF274/SETDB1 complex bound to the SNORD116 cluster may protect the PWS-IC from DNA demethylation during early development. Our findings reveal novel epigenetic mechanisms that function to repress the maternal 15q11-q13 region.]]>
Mon, 04 Aug 2014 00:00:00 PDT
Multi-ethnic fine-mapping of 14 central adiposity loci. Liu CT, Buchkovich ML, Winkler TW, Heid IM,  ,  , Borecki IB, Fox CS, Mohlke KL, North KE, Adrienne Cupples L
Hum Mol Genet (Sep 2014)

The Genetic Investigation of Anthropometric Traits (GIANT) consortium identified 14 loci in European Ancestry (EA) individuals associated with waist-to-hip ratio (WHR) adjusted for body mass index. These loci are wide and narrowing the signals remains necessary. Twelve of 14 loci identified in GIANT EA samples retained strong associations with WHR in our joint EA/individuals of African Ancestry (AA) analysis (log-Bayes factor >6.1). Trans-ethnic analyses at five loci (TBX15-WARS2, LYPLAL1, ADAMTS9, LY86 and ITPR2-SSPN) substantially narrowed the signals to smaller sets of variants, some of which are in regions that have evidence of regulatory activity. By leveraging varying linkage disequilibrium structures across different populations, single-nucleotide polymorphisms (SNPs) with strong signals and narrower credible sets from trans-ethnic meta-analysis of central obesity provide more precise localizations of potential functional variants and suggest a possible regulatory role. Meta-analysis results for WHR were obtained from 77 167 EA participants from GIANT and 23 564 AA participants from the African Ancestry Anthropometry Genetics Consortium. For fine mapping we interrogated SNPs within ±250 kb flanking regions of 14 previously reported index SNPs from loci discovered in EA populations by performing trans-ethnic meta-analysis of results from the EA and AA meta-analyses. We applied a Bayesian approach that leverages allelic heterogeneity across populations to combine meta-analysis results and aids in fine-mapping shared variants at these locations. We annotated variants using information from the ENCODE Consortium and Roadmap Epigenomics Project to prioritize variants for possible functionality.]]>
Mon, 04 Aug 2014 00:00:00 PDT
The environmental roots of non-communicable diseases (NCDs) and the epigenetic impacts of globalization. Vineis P, Stringhini S, Porta M
Environ Res (Aug 2014)

Non-communicable diseases (NCDs) are increasing worldwide. We hypothesize that environmental factors (including social adversity, diet, lack of physical activity and pollution) can become "embedded" in the biology of humans. We also hypothesize that the "embedding" partly occurs because of epigenetic changes, i.e., durable changes in gene expression patterns. Our concern is that once such factors have a foundation in human biology, they can affect human health (including NCDs) over a long period of time and across generations.]]>
Fri, 01 Aug 2014 00:00:00 PDT
The impact of first trimester phthalate and phenol exposure on IGF2/H19 genomic imprinting and birth outcomes. LaRocca J, Binder AM, McElrath TF, Michels KB
Environ Res (Aug 2014)

Genomic imprinting leads to parent-of-origin specific gene expression and is determined by epigenetic modification of genes. The paternally expressed gene insulin-like growth-factor 2 (IGF2) is located about ~100kb from the maternally expressed non-coding gene H19 on human chromosome 11, and both genes play major roles in embryonic and placental growth. Given adverse gestational environments can influence DNA methylation patterns in extra-embryonic tissues, we hypothesized that prenatal exposure to endocrine disrupting chemicals (EDCs) alters H19 and IGF2 methylation in placenta. Our study was restricted to a total of 196 women co-enrolled in the Predictors of Preeclampsia Study and the Harvard Epigenetic Birth Cohort. First trimester urine concentrations of 8 phenols and 11 phthalate metabolites were measured and used to characterize EDC exposure profiles. We assessed methylation of differentially methylated regions (DMRs) by pyrosequencing of H19, IGF2DMR0, and IGF2DMR2 and correlated values with phenol and phthalate metabolites. We also assessed overall expression and allele-specific expression of H19 and IGF2. We found several significant associations between DNA methylation and additive biomarker measurements. A significant decrease in H19 methylation was associated with high levels of the sum (Σ) of phthalate metabolites and metabolites of low molecular weight (LMW) phthalates. Σphthalate and LMW phthalate concentrations were inversely associated with IGF2DMR0 methylation values. Variation in methylation was not associated with changes in allele-specific expression. However increased deviation of allele-specific expression of H19 was associated with Σdi(2-ethylhexyl) phthalate metabolites and high molecular weight phthalates. Neither methylation nor expression of these imprinted regions had a significant impact on birth length or birth weight. Overall, our study provides new insight into an epigenetic mechanism that occurs following EDC exposure.]]>
Fri, 01 Aug 2014 00:00:00 PDT
Imprinted loci in domestic livestock species as epigenomic targets for artificial selection of complex traits. Magee DA, Spillane C, Berkowicz EW, Sikora KM, MacHugh DE
Anim Genet (Aug 2014)

The phenomenon of genomic imprinting, whereby a subset of mammalian genes display parent-of-origin-specific monoallelic expression, is one of the most active areas of epigenetics research. Over the past two decades, more than 100 imprinted mammalian genes have been identified, while considerable advances have been made in elucidating the molecular mechanisms governing imprinting. These studies have helped to unravel the epigenome - a separate layer of regulatory information contained in eukaryotic chromosomes that influences gene expression and phenotypes without involving changes to the underlying DNA sequence. Although most studies of genomic imprinting in mammals have focussed on mouse models or human biomedical disorders, there is burgeoning interest in the phenotypic effects of imprinted genes in domestic livestock species. In particular, research has focused on imprinted genes influencing foetal growth and development, which are associated with economically important production traits in cattle, sheep and pigs. These findings, when coupled with the data emerging from the various different livestock genome projects, have major implications for the future of animal breeding, health and management. Here, we review current scientific knowledge regarding genomic imprinting in livestock species and evaluate how this information can be used in modern livestock improvement programmes.]]>
Mon, 28 Jul 2014 00:00:00 PDT
A high-resolution whole-genome map of the distinctive epigenomic landscape induced by butyrate in bovine cells. Shin JH, Xu L, Li RW, Gao Y, Bickhart D, Liu GE, Baldwin R, Li CJ
Anim Genet (Aug 2014)

This report presents a study utilizing next-generation sequencing technology, combined with chromatin immunoprecipitation (ChIP-seq) technology to analyze histone modification induced by butyrate and to construct a high-definition map of the epigenomic landscape with normal histone H3 and H4 and their variants in bovine cells at the whole-genome scale. A total of 10 variants of histone H3 and H4 modifications were mapped at the whole-genome scale (acetyl-H3K18-ChIP-seq, trimethy-H3K9, histone H4 ChIP-seq, acetyl-H4K5 ChIP-seq, acetyl-H4K12 ChIP-seq, acetyl-H4K16 ChIP-seq, histone H3 ChIP-seq, acetyl H3H9 ChIP-seq, acetyl H3K27 ChIP-seq and tetra-acetyl H4 ChIP-seq). Integrated experiential data and an analysis of histone and histone modification at a single base resolution across the entire genome are presented. We analyzed the enriched binding regions in the proximal promoter (within 5 kb upstream or at the 5'-untranslated region from the transcriptional start site (TSS)), and the exon, intron and intergenic regions (defined by regions 25 kb upstream and 10 kb downstream from the TSS). A de novo search for the binding motif of the 10 ChIP-seq datasets discovered numerous motifs from each of the ChIP-seq datasets. These consensus sequences indicated that histone modification at different locations changes the histone H3 and H4 binding preferences. Nevertheless, a high degree of conservation in histone binding also was presented in these motifs. This first extensive epigenomic landscape mapping in bovine cells offers a new framework and a great resource for testing the role of epigenomes in cell function and transcriptomic regulation.]]>
Mon, 28 Jul 2014 00:00:00 PDT
The evolution of genomic imprinting: costs, benefits and long-term consequences. Holman L, Kokko H
Biol Rev Camb Philos Soc (Aug 2014)

Genomic imprinting refers to a pattern of gene expression in which a specific parent's allele is either under-expressed or completely silenced. Imprinting is an evolutionary conundrum because it appears to incur the costs of diploidy (e.g. presenting a larger target than haploidy to mutations) while foregoing its benefits (protection from harmful recessive mutations). Here, we critically evaluate previously proposed evolutionary benefits of imprinting and suggest some additional ones. We discuss whether each benefit is capable of explaining both the origin and maintenance of imprinting, and examine how the different benefits interact. We then outline the many costs of imprinting. Simple models show that circulating deleterious recessives can prevent the initial spread of imprinting, even if imprinting would be evolutionarily stable if it could persist long enough to purge these. We also show that imprinting can raise or lower the mutation load, depending on the selective regime and the degree of dominance. We finish by discussing the population-level consequences of imprinting, which can be both positive and negative. Imprinting offers many insights into evolutionary conflict, the interaction between individual- and population-level fitness effects, and the 'gene's-eye view' of evolution.]]>
Mon, 21 Jul 2014 00:00:00 PDT
Two deletions overlapping a distant FOXF1 enhancer unravel the role of lncRNA LINC01081 in etiology of alveolar capillary dysplasia with misalignment of pulmonary veins. Szafranski P, Dharmadhikari AV, Wambach JA, Towe CT, White FV, Grady RM, Eghtesady P, Cole FS, Deutsch G, Sen P, Stankiewicz P
Am J Med Genet A (Aug 2014)

Position effects due to disruption of distant cis-regulatory regions have been reported for over 40 human gene loci; however, the underlying mechanisms of long-range gene regulation remain largely unknown. We report on two patients with alveolar capillary dysplasia with misalignment of pulmonary veins (ACDMPV) caused by overlapping genomic deletions that included a distant FOXF1 transcriptional enhancer mapping 0.3 Mb upstream to FOXF1 on 16q24.1. In one patient with atypical late-onset ACDMPV, a ∼1.5 Mb deletion removed the proximal 43% of this enhancer, leaving the lung-specific long non-coding RNA (lncRNA) gene LINC01081 intact. In the second patient with severe neonatal-onset ACDMPV, an overlapping ∼194 kb deletion disrupted LINC01081. Both deletions arose de novo on maternal copy of the chromosome 16, supporting the notion that FOXF1 is paternally imprinted in the human lungs. RNAi-mediated knock-down of LINC01081 in normal fetal lung fibroblasts showed that this lncRNA positively regulates FOXF1 transcript level, further indicating that decrease in LINC01081 expression can contribute to development of ACDMPV. © 2014 Wiley Periodicals, Inc.]]>
Mon, 21 Jul 2014 00:00:00 PDT
Oxidized low-density lipoprotein induces long-term proinflammatory cytokine production and foam cell formation via epigenetic reprogramming of monocytes. Bekkering S, Quintin J, Joosten LA, van der Meer JW, Netea MG, Riksen NP
Arterioscler Thromb Vasc Biol (Aug 2014)

Although the role of monocytes in the pathogenesis of atherosclerosis is well established, the persistent vascular inflammation remains largely unexplained. Recently, our group reported that stimulation of monocytes with various microbial products can induce a long-lasting proinflammatory phenotype via epigenetic reprogramming, a process termed trained immunity. We now hypothesize that oxidized low-density lipoprotein (oxLDL) also induces a long-lasting proinflammatory phenotype in monocytes, which accelerates atherosclerosis by proinflammatory cytokine production and foam cell formation.]]>
Thu, 17 Jul 2014 00:00:00 PDT
The ways of action of long non-coding RNAs in cytoplasm and nucleus. Zhang K, Shi ZM, Chang YN, Hu ZM, Qi HX, Hong W
Gene (Aug 2014)

Over the past fifteen years, small regulatory RNAs, such as siRNA and miRNA, have been extensively investigated and the underlying molecular mechanisms have been well documented, suggesting that ncRNAs play a major function in many cellular processes. An expanding body of evidence reveals that long non-coding RNAs (lncRNAs), once described as dark matter, are involved in diverse cellular progresses, including regulation of gene expression, dosage compensation, genomic imprinting, nuclear organization and nuclear-cytoplasm trafficking via a number of complex mechanisms. The emerging links between lncRNAs and diseases as well as their tissue-specific expression patterns also indicate that lncRNAs comprise a core transcriptional regulatory circuitry. The function of lncRNAs is based on their sequence and structure; and they can combine with DNA, RNA, and proteins both in the nucleus and the cytoplasm. However, detailed insights into their biological and mechanistic functions are only beginning to emerge. In this review, we will mainly talk about diverse ways of action of lncRNAs in different sub-cellular locations and provide clues for following studies.]]>
Tue, 08 Jul 2014 00:00:00 PDT