'; ?> 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 Sat, 21 Apr 2018 09:28:56 EDT Sat, 21 Apr 2018 09:28:56 EDT jirtle@radonc.duke.edu james001@jirtle.com Repositioning of difluorinated propanediones as inhibitors of histone methyltransferases and their biological evaluation in human leukemic cell lines. Pal T, Sharda A, Khade B, Ramaa CS, Gupta S
Anticancer Agents Med Chem (Apr 2018)

Cancer chemotherapy is associated with limitations like dose dependent host-tissue toxicity, multiple drug resistance and tumor heterogeneity. Hence, it is imperative to unearth novel targets to cure cancer. At present, 'pharmaco-epigenomics' constitutes the hope in cancer treatment owing to epigenetic deregulation- a reversible process, suspected of playing a role in malignancy. In this research work, we have used the fundamentals of drug repurposing for a set of our previously synthesized difluorinated propanediones and evaluated them for their histone methyltransferase inhibitory potential in leukemic cell lines. A small molecule inhibitor PR-4, at a concentration of 1 and 10μM, has shown to alter the methylation levels in two leukemic cell lines, one of histiocytic lymphoma (U937) and other of acute T-cell leukemia (JURKAT). Treatment with the compound shows an increase in G2/M population and a subsequent decrease in the G0/G1 population 24h post treatment in U937. In JURKAT, an increase in both G2/M and S phase population at 16 and 24h time point was observed. The sub-G1 population showed a steady rise with increase in dose and prolonged time intervals in U937 and JURKAT cell lines. In SRB assay, the moiety showed a cell growth of 42.6 % and 53.4% comparable to that of adriamycin; 44.5% and 53.2% in U937 and JURKAT, respectively. The apoptosis pattern suggests that this molecule could emerge as a potential anticancer agent by targeting histone methyltransferases. The molecule PR-4 could be a lead in developing more histone lysine methyltransferases inhibitors with potential to be anti-carcinogenic agents.]]>
Wed, 31 Dec 1969 19:00:00 EST
Meg3 Non-coding RNA Expression Controls Imprinting by Preventing Transcriptional Upregulation in cis. Sanli I, Lalevée S, Cammisa M, Perrin A, Rage F, Llères D, Riccio A, Bertrand E, Feil R
Cell Rep (Apr 2018)

Although many long non-coding RNAs (lncRNAs) are imprinted, their roles often remain unknown. The Dlk1-Dio3 domain expresses the lncRNA Meg3 and multiple microRNAs and small nucleolar RNAs (snoRNAs) on the maternal chromosome and constitutes an epigenetic model for development. The domain's Dlk1 (Delta-like-1) gene encodes a ligand that inhibits Notch1 signaling and regulates diverse developmental processes. Using a hybrid embryonic stem cell (ESC) system, we find that Dlk1 becomes imprinted during neural differentiation and that this involves transcriptional upregulation on the paternal chromosome. The maternal Dlk1 gene remains poised. Its protection against activation is controlled in cis by Meg3 expression and also requires the H3-Lys-27 methyltransferase Ezh2. Maternal Meg3 expression additionally protects against de novo DNA methylation at its promoter. We find that Meg3 lncRNA is partially retained in cis and overlaps the maternal Dlk1 in embryonic cells. Combined, our data evoke an imprinting model in which allelic lncRNA expression prevents gene activation in cis.]]>
Wed, 31 Dec 1969 19:00:00 EST
Oxygen-induced alterations in the expression of chromatin modifying enzymes and the transcriptional regulation of imprinted genes. Skiles WM, Kester A, Pryor JH, Westhusin ME, Golding MC, Long CR
Gene Expr Patterns (Jun 2018)

Embryo culture and assisted reproductive technologies have been associated with a disproportionately high number of epigenetic abnormalities in the resulting offspring. However, the mechanisms by which these techniques influence the epigenome remain poorly defined. In this study, we evaluated the capacity of oxygen concentration to influence the transcriptional control of a selection of key enzymes regulating chromatin structure. In mouse embryonic stem cells, oxygen concentrations modulated the transcriptional regulation of the TET family of enzymes, as well as the de novo methyltransferase Dnmt3a. These transcriptional changes were associated with alterations in the control of multiple imprinted genes, including H19, Igf2, Igf2r, and Peg3. Similarly, exposure of in vitro produced bovine embryos to atmospheric oxygen concentrations was associated with disruptions in the transcriptional regulation of TET1, TET3, and DNMT3a, along with the DNA methyltransferase co-factor HELLS. In addition, exposure to high oxygen was associated with alterations in the abundance of transcripts encoding members of the Polycomb repressor complex (EED and EZH2), the histone methyltransferase SETDB1 and multiple histone demethylases (KDM1A, KDM4B, and KDM4C). These disruptions were accompanied by a reduction in embryo viability and suppression of the pluripotency genes NANOG and SOX2. These experiments demonstrate that oxygen has the capacity to modulate the transcriptional control of chromatin modifying genes involved in the establishment and maintenance of both pluripotency and genomic imprinting.]]>
Wed, 31 Dec 1969 19:00:00 EST
Epigenome dysregulation in cholangiocarcinoma. O'Rourke CJ, Munoz-Garrido P, Aguayo EL, Andersen JB
Biochim Biophys Acta (Apr 2018)

Epigenomics is a fast-evolving field of research that has lately attracted considerable interest, mainly due to the reversibility of epigenetic marks. Clinically, among solid tumors, the field is still limited. In cholangiocarcinoma (CCA) it is well known that the epigenetic landscape is deregulated both during carcinogenesis and disease progression as a consequence of aberrant mechanisms leading to genome instability. In this article, we will briefly review the molecular alterations that have been described in the transformation of normal cholangiocytes into malignant derivatives, focusing on the role of non-coding RNA (ncRNA) interactions, DNA methylation, post-translational modifications (PTMs) of histones and chromatin remodeling complexes.]]>
Wed, 31 Dec 1969 19:00:00 EST
Integrated 'omics analysis reveals new drug-induced mitochondrial perturbations in human hepatocytes. Wolters JEJ, van Breda SGJ, Grossmann J, Fortes C, Caiment F, Kleinjans JCS
Toxicol Lett (Jun 2018)

We performed a multiple 'omics study by integrating data on epigenomic, transcriptomic, and proteomic perturbations associated with mitochondrial dysfunction in primary human hepatocytes caused by the liver toxicant valproic acid (VPA), to deeper understand downstream events following epigenetic alterations in the mitochondrial genome. Furthermore, we investigated persistence of cross-omics changes after terminating drug treatment. Upon transient methylation changes of mitochondrial genes during VPA-treatment, increasing complexities of gene-interaction networks across time were demonstrated, which normalized during washout. Furthermore, co-expression between genes and their corresponding proteins increased across time. Additionally, in relation to persistently decreased ATP production, we observed decreased expression of mitochondrial complex I and III-V genes. Persistent transcripts and proteins were related to citric acid cycle and β-oxidation. In particular, we identified a potential novel mitochondrial-nuclear signaling axis, MT-CO2-FN1-MYC-CPT1. In summary, this cross-omics study revealed dynamic responses of the mitochondrial epigenome to an impulse toxicant challenge resulting in persistent mitochondrial dysfunctioning. Moreover, this approach allowed for discriminating between the toxic effect of VPA and adaptation.]]>
Wed, 31 Dec 1969 19:00:00 EST
Nucleosome-level 3D organization of the genome. Ohno M, Priest DG, Taniguchi Y
Biochem Soc Trans (Apr 2018)

Nucleosomes are the unitary structures of chromosome folding, and their arrangements are intimately coupled to the regulation of genome activities. Conventionally, structural analyses using electron microscopy and X-ray crystallography have been used to study such spatial nucleosome arrangements. In contrast, recent improvements in the resolution of sequencing-based methods allowed investigation of nucleosome arrangements separately at each genomic locus, enabling exploration of gene-dependent regulation mechanisms. Here, we review recent studies on nucleosome folding in chromosomes from these two methodological perspectives: conventional structural analyses and DNA sequencing, and discuss their implications for future research.]]>
Wed, 31 Dec 1969 19:00:00 EST
Piecing together cis-regulatory networks: insights from epigenomics studies in plants. Huang SC, Ecker JR
Wiley Interdiscip Rev Syst Biol Med (May 2018)

5-Methylcytosine, a chemical modification of DNA, is a covalent modification found in the genomes of both plants and animals. Epigenetic inheritance of phenotypes mediated by DNA methylation is well established in plants. Most of the known mechanisms of establishing, maintaining and modifying DNA methylation have been worked out in the reference plant Arabidopsis thaliana. Major functions of DNA methylation in plants include regulation of gene expression and silencing of transposable elements (TEs) and repetitive sequences, both of which have parallels in mammalian biology, involve interaction with the transcriptional machinery, and may have profound effects on the regulatory networks in the cell. Methylome and transcriptome dynamics have been investigated in development and environmental responses in Arabidopsis and agriculturally and ecologically important plants, revealing the interdependent relationship among genomic context, methylation patterns, and expression of TE and protein coding genes. Analyses of methylome variation among plant natural populations and species have begun to quantify the extent of genetic control of methylome variation vs. true epimutation, and model the evolutionary forces driving methylome evolution in both short and long time scales. The ability of DNA methylation to positively or negatively modulate binding affinity of transcription factors (TFs) provides a natural link from genome sequence and methylation changes to transcription. Technologies that allow systematic determination of methylation sensitivities of TFs, in native genomic and methylation context without confounding factors such as histone modifications, will provide baseline datasets for building cell-type- and individual-specific regulatory networks that underlie the establishment and inheritance of complex traits. This article is categorized under: Laboratory Methods and Technologies > Genetic/Genomic Methods Biological Mechanisms > Regulatory Biology.]]>
Wed, 31 Dec 1969 19:00:00 EST
Novel imprinted single CpG sites found by global DNA methylation analysis in human parthenogenetic induced pluripotent stem cells. Choi NY, Bang JS, Lee HJ, Park YS, Lee M, Jeong D, Ko K, Han DW, Chung HM, Kim GJ, Shim SH, Hwang HS, Ko K
Epigenetics (Apr 2018)

Genomic imprinting is the process of epigenetic modification whereby genes are expressed in a parent-of-origin dependent manner; it plays an important role in normal growth and development. Parthenogenetic embryos contain only the maternal genome. Parthenogenetic embryonic stem cells could be useful for studying imprinted genes. In humans, ovarian mature cystic teratomas originate from parthenogenetic activation of oocytes; they are composed of highly differentiated mature tissues containing all three germ layers. To establish human parthenogenetic induced pluripotent stem cell lines (PgHiPSCs), we generated parthenogenetic fibroblasts from ovarian teratoma tissues. We compared global DNA methylation status of PgHiPSCs with that of biparental human induced pluripotent stem cells by using Illumina Infinium HumanMethylation450 BeadChip array. This analysis identified novel single imprinted CpG sites. We further tested DNA methylation patterns of two of these sites using bisulfite sequencing and described novel candidate imprinted CpG sites. These results confirm that PgHiPSCs are a powerful tool for identifying imprinted genes and investigating their roles in human development and diseases.]]>
Wed, 31 Dec 1969 19:00:00 EST
ASB1 differential methylation in ischaemic cardiomyopathy: relationship with left ventricular performance in end-stage heart failure patients. Ortega A, Tarazón E, Gil-Cayuela C, Martínez-Dolz L, Lago F, González-Juanatey JR, Sandoval J, Portolés M, Roselló-Lletí E, Rivera M
ESC Heart Fail (Apr 2018)

Ischaemic cardiomyopathy (ICM) leads to impaired contraction and ventricular dysfunction, causing high rates of morbidity and mortality. Epigenomics allows the identification of epigenetic signatures in human diseases. We analyse the differential epigenetic patterns of the ASB gene family in ICM patients and relate these alterations to their haemodynamic and functional status.]]>
Wed, 31 Dec 1969 19:00:00 EST
The effects of DNA methylation on human psychology. Kader F, Ghai M, Maharaj L
Behav Brain Res (07 2018)

DNA methylation is a fundamental epigenetic modification in the human genome; pivotal in development, genomic imprinting, X inactivation, chromosome stability, gene expression and methylation aberrations are involved in an array of human diseases. Methylation at promoters is associated with transcriptional repression, whereas gene body methylation is generally associated with gene expression. Extrinsic factors such as age, diets and lifestyle affect DNA methylation which consequently alters gene expression. Stress, anxiety, depression, life satisfaction, emotion among numerous other psychological factors also modify DNA methylation patterns. This correlation is frequently investigated in four candidate genes; NR3C1, SLC6A4, BDNF and OXTR, since regulation of these genes directly impact responses to social situations, stress, threats, behaviour and neural functions. Such studies underpin the hypothesis that DNA methylation is involved in deviant human behaviour, psychological and psychiatric conditions. These candidate genes may be targeted in future to assess the correlation between methylation, social experiences and long-term behavioural phenotypes in humans; and may potentially serve as biomarkers for therapeutic intervention.]]>
Wed, 31 Dec 1969 19:00:00 EST
'Omic' technologies as a helpful tool in radioecological research. Volkova PY, Geras'kin SA
J Environ Radioact (Apr 2018)

This article presents a brief review of the modern 'omic' technologies, namely genomics, epigenomics, transcriptomics, proteomics, and metabolomics, as well as the examples of their possible use in radioecology. For each technology, a short description of advances, limitations, and instrumental applications is given. In addition, the review contains examples of successful use of 'omic' technologies in the assessment of biological effects of pollutants in the field conditions.]]>
Wed, 31 Dec 1969 19:00:00 EST
OBscure but not OBsolete: Perturbations of the frontal cortex in common between rodent olfactory bulbectomy model and major depression. Rajkumar R, S Dawe G
J Chem Neuroanat (Apr 2018)

Olfactory bulbectomy (OBX) has been used as a model of depression over several decades. This model presupposes a mechanism that is still not proven in clinical depression. A wealth of clinical literature has focused on the derangements in frontal cortex (prefrontal, orbitofrontal and anterior cingulate cortices) associated with depression. In this comprehensive review, anatomical, electrophysiological and molecular sequelae of bulbectomy in the rodent frontal cortex are explored and compared with findings on brains of humans with major depression. Certain commonalities in neurobiological features of the perturbed frontal cortex in the bulbectomised rodent and the depressed human brain are evident. Also, meta-analysis reports on clinical studies on depressed patients provide prima facie evidence that perturbations in the frontal cortex are associated with major depression. Analysing the pattern of perturbations in the chemical neuroanatomy of the frontal cortex will contribute to understanding of the neurobiology of depression. Revisiting the OBX model of depression to examine these neurobiological changes in frontal cortex with contemporary imaging, proteomics, lipidomics, metabolomics and epigenomics technologies is proposed as an approach to enhance the translational value of this animal model to facilitate identification of targets and biomarkers for clinical depression.]]>
Wed, 31 Dec 1969 19:00:00 EST
DNA Methylation and Histone Modification in Hypertension. Stoll S, Wang C, Qiu H
Int J Mol Sci (Apr 2018)

Systemic hypertension, which eventually results in heart failure, renal failure or stroke, is a common chronic human disorder that particularly affects elders. Although many signaling pathways involved in the development of hypertension have been reported over the past decades, which has led to the implementation of a wide variety of anti-hypertensive therapies, one half of all hypertensive patients still do not have their blood pressure controlled. The frontier in understanding the molecular mechanisms underlying hypertension has now advanced to the level of epigenomics. Particularly, increasing evidence is emerging that DNA methylation and histone modifications play an important role in gene regulation and are involved in alteration of the phenotype and function of vascular cells in response to environmental stresses. This review seeks to highlight the recent advances in our knowledge of the epigenetic regulations and mechanisms of hypertension, focusing on the role of DNA methylation and histone modification in the vascular wall. A better understanding of the epigenomic regulation in the hypertensive vessel may lead to the identification of novel target molecules that, in turn, may lead to novel drug discoveries for the treatment of hypertension.]]>
Wed, 31 Dec 1969 19:00:00 EST
The Key Role of Epigenetics in Human Disease Prevention and Mitigation. Feinberg AP
N Engl J Med (04 2018)

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Wed, 31 Dec 1969 19:00:00 EST
Defining Cell Identity with Single Cell Omics. Mincarelli L, Lister A, Lipscombe J, Macaulay IC
Proteomics (Apr 2018)

Cells are a fundamental unit of life, and the ability to study the phenotypes and behaviours of individual cells is crucial to understanding the workings of complex biological systems. Cell phenotypes (epigenomic, transcriptomic, proteomic and metabolomic) exhibit dramatic heterogeneity between and within the different cell types and states underlying cellular functional diversity. Cell genotypes can also display heterogeneity throughout an organism, in the form of somatic genetic variation - most notably in the emergence and evolution of tumours. Recent technical advances in single-cell isolation and the development of omics approaches sensitive enough to reveal these aspects of cell identity have enabled a revolution in the study of multicellular systems. In this review, we discuss the technologies available to resolve the genomes, epigenomes, transcriptomes, proteomes and metabolomes of single cells from a wide variety of living systems. This article is protected by copyright. All rights reserved.]]>
Wed, 31 Dec 1969 19:00:00 EST
LncRNAs: Proverbial Genomic "Junk" or Key Epigenetic Regulators During Cardiac Fibrosis in Diabetes? Biswas S, Thomas AA, Chakrabarti S
Front Cardiovasc Med (2018)

Long non-coding RNAs (lncRNAs) are critical regulators in a multitude of biological processes. Recent evidences demonstrate potential pathogenetic implications of lncRNAs in diabetic cardiomyopathy (DCM); however, the majority of lncRNAs have not been comprehensively characterized. While the precise molecular mechanisms underlying the functions of lncRNAs remain to be deciphered in DCM, emerging data in other pathophysiological conditions suggests that lncRNAs can have versatile features such as genomic imprinting, acting as guides for certain histone-modifying complexes, serving as scaffolds for specific molecules, or acting as molecular sponges. In an effort to better understand these features of lncRNAs in the context of DCM, our review will first summarize some of the key molecular alterations that occur during fibrosis in the diabetic heart (extracellular proteins and endothelial-to-mesenchymal transitioning), followed by a review of the current knowledge on the crosstalk between lncRNAs and major epigenetic mechanisms (histone methylation, histone acetylation, DNA methylation, and microRNAs) within this fibrotic process.]]>
Wed, 31 Dec 1969 19:00:00 EST
PREDICTD PaRallel Epigenomics Data Imputation with Cloud-based Tensor Decomposition. Durham TJ, Libbrecht MW, Howbert JJ, Bilmes J, Noble WS
Nat Commun (Apr 2018)

The Encyclopedia of DNA Elements (ENCODE) and the Roadmap Epigenomics Project seek to characterize the epigenome in diverse cell types using assays that identify, for example, genomic regions with modified histones or accessible chromatin. These efforts have produced thousands of datasets but cannot possibly measure each epigenomic factor in all cell types. To address this, we present a method, PaRallel Epigenomics Data Imputation with Cloud-based Tensor Decomposition (PREDICTD), to computationally impute missing experiments. PREDICTD leverages an elegant model called "tensor decomposition" to impute many experiments simultaneously. Compared with the current state-of-the-art method, ChromImpute, PREDICTD produces lower overall mean squared error, and combining the two methods yields further improvement. We show that PREDICTD data captures enhancer activity at noncoding human accelerated regions. PREDICTD provides reference imputed data and open-source software for investigating new cell types, and demonstrates the utility of tensor decomposition and cloud computing, both promising technologies for bioinformatics.]]>
Wed, 31 Dec 1969 19:00:00 EST
Experience-dependent neuroplasticity of the developing hypothalamus: integrative epigenomic approaches. Vogel Ciernia A, Laufer BI, Dunaway KW, Mordaunt CE, Coulson RL, Totah TS, Stolzenberg DS, Frahm J, Singh-Taylor A, Baram TZ, LaSalle JM, Yasui DH
Epigenetics (Apr 2018)

Augmented maternal care during the first postnatal week promotes life-long stress resilience and improved memory compared with the outcome of routine rearing conditions. Recent evidence suggests that this programming commences with altered synaptic connectivity of stress sensitive hypothalamic neurons. However, the epigenomic basis of the long-lived consequences is not well understood. Here, we employed whole-genome bisulfite sequencing (WGBS), RNA-sequencing (RNA-seq), and a multiplex microRNA (miRNA) assay to examine the effects of augmented maternal care on DNA cytosine methylation, gene expression, and miRNA expression. A total of 9,439 differentially methylated regions (DMRs) associated with augmented maternal care were identified in male offspring hypothalamus, as well as a modest but significant decrease in global DNA methylation. Differentially methylated and expressed genes were enriched for functions in neurotransmission, neurodevelopment, protein synthesis, and oxidative phosphorylation, as well as known stress response genes. Twenty prioritized genes were identified as highly relevant to the stress resiliency phenotype. This combined unbiased approach enabled the discovery of novel genes and gene pathways that advance our understanding of the epigenomic mechanisms underlying the effects of maternal care on the developing brain.]]>
Wed, 31 Dec 1969 19:00:00 EST
Classification of heterogeneous genetic variations of microRNA regulome in cancer. Hrovatin K, Kunej T
Cancer Lett (Apr 2018)

Genetic variations and differential expression of miRNA regulome components are associated with cancer. Thus miRNA based diagnosis and treatments have been proposed. However, to better explore these options, the molecular changes in miRNA regulome must be understood. MicroRNAs can be involved in regulation of oncogenes and tumour suppressors. As each miRNA targets broad range of genes, minor changes in miRNAs can have great effects, contributing to cell transformation. Many genetic variants of miRNA regulome have been reported to be associated with cancer, but this information needs to be systematized. Therefore, we here classify different types of genetic variations of miRNA regulome in cancer. Genetic variations are comprised of structural and short polymorphisms and changes in epigenetic landscape. Additionally, unexplained differential expression is often reported. These alterations affect miRNA genes and their regulatory elements, processing machinery, degradation machinery, and targets, leading to changes in miRNA silencing. However, miRNA regulome components are not equally explored. A systematic overview over miRNA regulome can contribute to more targeted study design and understanding of miRNA function. We also present treatments and diagnosis based on miRNA regulome genetic variability and expression.]]>
Wed, 31 Dec 1969 19:00:00 EST
Evidence establishing a link between prenatal and early-life stress and asthma development. Rosa MJ, Lee AG, Wright RJ
Curr Opin Allergy Clin Immunol (Apr 2018)

The objective of this review is to provide an update on our evolving understanding of the effects of stress in pregnancy and during early development on the onset of asthma-related phenotypes across childhood, adolescence, and into early adulthood.]]>
Wed, 31 Dec 1969 19:00:00 EST