'; ?> 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 Sun, 14 Sep 2014 14:33:05 PDT Sun, 14 Sep 2014 14:33:05 PDT jirtle@radonc.duke.edu james001@jirtle.com Impairment of adipose tissue in Prader-Willi syndrome rescued by growth hormone treatment. Cadoudal T, Buléon M, Sengenès C, Diene G, Desneulin F, Molinas C, Eddiry S, Conte-Auriol F, Daviaud D, Martin PG, Bouloumié A, Salles JP, Tauber M, Valet P
Int J Obes (Lond) (Sep 2014)

Prader-Willi syndrome (PWS) results from abnormalities in the genomic imprinting process leading to hypothalamic dysfunction with an alteration of growth hormone (GH) secretion. PWS is associated with early morbid obesity and short stature which can be efficiently improved with GH treatment.]]>
Wed, 10 Sep 2014 00:00:00 PDT
Single Molecule and Single Cell Epigenomics. Hyun BR, McElwee JL, Soloway PD
Methods (Sep 2014)

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.]]>
Wed, 10 Sep 2014 00:00:00 PDT
Dnmt3b Prefers Germ Line Genes and Centromeric Regions: Lessons from the ICF Syndrome and Cancer and Implications for Diseases. Walton EL, Francastel C, Velasco G
Biology (Basel) (2014)

The correct establishment and maintenance of DNA methylation patterns are critical for mammalian development and the control of normal cell growth and differentiation. DNA methylation has profound effects on the mammalian genome, including transcriptional repression, modulation of chromatin structure, X chromosome inactivation, genomic imprinting, and the suppression of the detrimental effects of repetitive and parasitic DNA sequences on genome integrity. Consistent with its essential role in normal cells and predominance at repetitive genomic regions, aberrant changes of DNA methylation patterns are a common feature of diseases with chromosomal and genomic instabilities. In this context, the functions of DNA methyltransferases (DNMTs) can be affected by mutations or alterations of their expression. DNMT3B, which is involved in de novo methylation, is of particular interest not only because of its important role in development, but also because of its dysfunction in human diseases. Expression of catalytically inactive isoforms has been associated with cancer risk and germ line hypomorphic mutations with the ICF syndrome (Immunodeficiency Centromeric instability Facial anomalies). In these diseases, global genomic hypomethylation affects repeated sequences around centromeric regions, which make up large blocks of heterochromatin, and is associated with chromosome instability, impaired chromosome segregation and perturbed nuclear architecture. The review will focus on recent data about the function of DNMT3B, and the consequences of its deregulated activity on pathological DNA hypomethylation, including the illicit activation of germ line-specific genes and accumulation of transcripts originating from repeated satellite sequences, which may represent novel physiopathological biomarkers for human diseases. Notably, we focus on cancer and the ICF syndrome, pathological contexts in which hypomethylation has been extensively characterized. We also discuss the potential contribution of these deregulated protein-coding and non-coding transcription programs to the perturbation of cellular phenotypes.]]>
Tue, 09 Sep 2014 00:00:00 PDT
What does genetics tell us about imprinting and the placenta connection? Varmuza S, Miri K
Cell Mol Life Sci (Sep 2014)

Genomic imprinting is an epigenetic gene silencing phenomenon that is specific to eutherians in the vertebrate lineage. The acquisition of both placentation and genomic imprinting has spurred interest in the possible evolutionary link for many years. In this review we examine the genetic evidence and find that while many imprinted domains are anchored by genes required for proper placenta development in a parent of origin fashion, an equal number of imprinted genes have no apparent function that depends on imprinting. Examination of recent data from studies of molecular and genetic mechanisms points to a maternal control of the selection and maintenance of imprint marks, reinforcing the importance of the oocyte in the healthy development of the placenta and fetus.]]>
Sun, 07 Sep 2014 00:00:00 PDT
Mendelian disorders of the epigenetic machinery: tipping the balance of chromatin States. Fahrner JA, Bjornsson HT
Annu Rev Genomics Hum Genet (Aug 2014)

Mendelian disorders of the epigenetic machinery are a newly delineated group of multiple congenital anomaly and intellectual disability syndromes resulting from mutations in genes encoding components of the epigenetic machinery. The gene products affected in these inherited conditions act in trans and are expected to have widespread epigenetic consequences. Many of these syndromes demonstrate phenotypic overlap with classical imprinting disorders and with one another. The various writer and eraser systems involve opposing players, which we propose must maintain a balance between open and closed chromatin states in any given cell. An imbalance might lead to disrupted expression of disease-relevant target genes. We suggest that classifying disorders based on predicted effects on this balance would be informative regarding pathogenesis. Furthermore, strategies targeted at restoring this balance might offer novel therapeutic avenues, taking advantage of available agents such as histone deacetylase inhibitors and histone acetylation antagonists.]]>
Thu, 04 Sep 2014 00:00:00 PDT
Emerging issues in public health genomics. Roberts JS, Dolinoy DC, Tarini BA
Annu Rev Genomics Hum Genet (Aug 2014)

This review highlights emerging areas of interest in public health genomics. First, we describe recent advances in newborn screening (NBS), with a focus on the practice and policy implications of current and future efforts to expand NBS programs (e.g., via next-generation sequencing). Next, we detail research findings from the rapidly progressing field of epigenetics and epigenomics, highlighting ways in which our emerging understanding in these areas could guide future intervention and research efforts in public health. We close by considering various ethical, legal, and social issues posed by recent developments in public health genomics; these include policies to regulate access to personal genomic information, the need to enhance genetic literacy in both health professionals and the public, and challenges in ensuring that the benefits (and burdens) of genomic discoveries and applications are equitably distributed. We also note needs for future genomic research that integrates across basic and social sciences.]]>
Thu, 04 Sep 2014 00:00:00 PDT
The mechanistic role of DNA methylation in myeloid leukemogenesis. Jasielec J, Saloura V, Godley LA
Leukemia (Sep 2014)

The importance of epigenetic aberrations in the pathogenesis of leukemias has been revealed by recurrent gene mutations that highlight epigenetic pathways as well as by the clinical success of therapies like 5-azacytidine and decitabine that work through epigenetic mechanisms. However, precise mechanisms of how gene mutations lead to leukemias and how epigenetic therapies induce clinical remissions are elusive. Current scientific inquiries that take advantage of techniques that can distinguish among the various covalent cytosine modifications at single base resolution are likely to shed light on the ways epigenetic pathways drive leukemogenesis as well as how the hypomethylating drugs induce clinical remissions. The hope is that these studies will also reveal which patients are likely to respond to epigenetic therapies. Thus, the future is likely to bring a new wave of diagnostic and prognostic tools that probe the epigenomics of leukemia to help clinicians in their management of patients.]]>
Wed, 03 Sep 2014 00:00:00 PDT
Improved drug therapy: triangulating phenomics with genomics and metabolomics. Monte AA, Brocker C, Nebert DW, Gonzalez FJ, Thompson DC, Vasiliou V
Hum Genomics (Sep 2014)

Embracing the complexity of biological systems has a greater likelihood to improve prediction of clinical drug response. Here we discuss limitations of a singular focus on genomics, epigenomics, proteomics, transcriptomics, metabolomics, or phenomics-highlighting the strengths and weaknesses of each individual technique. In contrast, 'systems biology' is proposed to allow clinicians and scientists to extract benefits from each technique, while limiting associated weaknesses by supplementing with other techniques when appropriate. Perfect predictive modeling is not possible, whereas modeling of intertwined phenomic responses using genomic stratification with metabolomic modifications may greatly improve predictive values for drug therapy. We thus propose a novel-integrated approach to personalized medicine that begins with phenomic data, is stratified by genomics, and ultimately refined by metabolomic pathway data. Whereas perfect prediction of efficacy and safety of drug therapy is not possible, improvements can be achieved by embracing the complexity of the biological system. Starting with phenomics, the combination of linking metabolomics to identify common biologic pathways and then stratifying by genomic architecture, might increase predictive values. This systems biology approach has the potential, in specific subsets of patients, to avoid drug therapy that will be either ineffective or unsafe.]]>
Wed, 03 Sep 2014 00:00:00 PDT
Nutrition, the brain and cognitive decline: insights from epigenetics. Dauncey MJ
Eur J Clin Nutr (Sep 2014)

Nutrition affects the brain throughout life, with profound implications for cognitive decline and dementia. These effects are mediated by changes in expression of multiple genes, and responses to nutrition are in turn affected by individual genetic variability. An important layer of regulation is provided by the epigenome: nutrition is one of the many epigenetic regulators that modify gene expression without changes in DNA sequence. Epigenetic mechanisms are central to brain development, structure and function, and include DNA methylation, histone modifications and non-protein-coding RNAs. They enable cell-specific and age-related gene expression. Although epigenetic events can be highly stable, they can also be reversible, highlighting a critical role for nutrition in prevention and treatment of disease. Moreover, they suggest key mechanisms by which nutrition is involved in the pathogenesis of age-related cognitive decline: many nutrients, foods and diets have both immediate and long-term effects on the epigenome, including energy status, that is, energy intake, physical activity, energy metabolism and related changes in body composition, and micronutrients involved in DNA methylation, for example, folate, vitamins B6 and B12, choline, methionine. Optimal brain function results from highly complex interactions between numerous genetic and environmental factors, including food intake, physical activity, age and stress. Future studies linking nutrition with advances in neuroscience, genomics and epigenomics should provide novel approaches to the prevention of cognitive decline, and treatment of dementia and Alzheimer's disease.European Journal of Clinical Nutrition advance online publication, 3 September 2014; doi:10.1038/ejcn.2014.173.]]>
Wed, 03 Sep 2014 00:00:00 PDT
Epigenetics in adaptive evolution and development: The interplay between evolving species and epigenetic mechanisms: Extract from Trygve Tollefsbol (ed.) (2011) Handbook of Epigenetics - The New Molecular and Medical Genetics. Chapter 26. Amsterdam, USA: Elsevier, pp. 423-446. House SH
Nutr Health (Sep 2014)

By comparing epigenetics of current species with fossil records across evolutionary transitions, we can gauge the moment of emergence of some novel mechanisms in evolution, and recognize that epigenetic mechanisms have a bearing on mutation. Understanding the complexity and changeability of these mechanisms, as well as the changes they can effect, is both fascinating and of vital practical benefit. Our most serious pandemics of so-called 'non-communicable' diseases - mental and cardiovascular disorders, obesity and diabetes, rooted in the 'metabolic syndrome' - are evidently related to effects on our evolutionary mechanisms of agricultural and food industrialization, modern lifestyle and diet. Pollution affects us directly as well as indirectly by its destruction of ecologically essential biosystems. Evidently such powerful conditions of existence have epigenetic effects on both our health and our continuing evolution. Such effects are most profound during reproductive and developmental processes, when levels of hormones, as affected by stress particularly, may be due to modern cultures in childbearing such as excessive intervention, separation, maternal distress and disruption of bonding. Mechanisms of genomic imprinting seem likely to throw light on problems in assisted reproductive technology, among other transgenerational effects.]]>
Tue, 02 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
Long Noncoding RNAs: Emerging Stars in Gene Regulation, Epigenetics and Human Disease. Bhan A, Mandal SS
ChemMedChem (Sep 2014)

Noncoding RNAs (ncRNAs) are classes of transcripts that are encoded by the genome and transcribed but never get translated into proteins. Though not translated into proteins, ncRNAs play pivotal roles in a variety of cellular functions. Here, we review the functions of long noncoding RNAs (lncRNAs) and their implications in various human diseases. Increasing numbers of studies demonstrate that lncRNAs play critical roles in regulation of protein-coding genes, maintenance of genomic integrity, dosage compensation, genomic imprinting, mRNA processing, cell differentiation, and development. Misregulation of lncRNAs is associated with a variety of human diseases, including cancer, immune and neurological disorders. Different classes of lncRNAs, their functions, mechanisms of action, and associations with different human diseases are summarized in detail, highlighting their as yet untapped potential in therapy.]]>
Fri, 29 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
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
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
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
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
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
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