Gestational Choline Supplementation Normalized Fetal Alcohol-Induced Alterations in Histone Modifications, DNA Methylation, and Proopiomelanocortin (POMC) Gene Expression in β-Endorphin-Producing POMC Neurons of the Hypothalamus

Mouse models of fetal alcohol spectrum disorders (FASD) have repeatedly identified genes with long-term changes in expression, DNA methylation, noncoding RNA, and histone modifications in response to neurodevelopmental alcohol exposure. Articulation of FASD is achieved via alcohol’s effect on gene expression, likely involving epigenetic regulation. The list of genes affected is large and heterogeneous, depending on experimental protocol. We present reanalysis and synthesis of results highlighting the Wnt transcription factor 7 like 2 (Tcf7l2) gene as uniquely compatible with hippocampal DNA methylation, histone modifications, and gene expression changes in a coordinated response to neurodevelopmental alcohol exposure. We data-mined the literature for Tcf7l2 alterations in response to prenatal alcohol exposure. Four studies identified changes in brain Tcf7l2 expression in different FASD models. Further, we performed an in silico TCF7L2 binding site analysis for FASD mouse model data sets. Seven of these published gene lists were significantly enriched for TCF7L2 binding, indicating potential functional relationships. Finally, TCF7L2 is involved in regulation of hundreds of genes, with a role in brain development, myelination, and neuronal function. Tcf7l2 may be involved in neurological defects associated with alcohol exposure via dysregulation of many genes through Wnt signaling. Further functional work is warranted to validate this model for FASD.

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Gene expression profiling of epigenetic chromatin modification enzymes and histone marks by cigarette smoke: implications for COPD and lung cancer

AJP Lung Cellular and Molecular Physiology ◽

10.1152/ajplung.00253.2016 ◽

2016 ◽

Vol 311 (6) ◽

pp. L1245-L1258 ◽

Cited By ~ 19

Author(s):

Isaac K. Sundar ◽

Irfan Rahman

Keyword(s):

Gene Expression ◽

Lung Cancer ◽

Dna Methylation ◽

Cigarette Smoke ◽

Histone Modifications ◽

Expression Patterns ◽

Chromatin Modification ◽

Gene Expression Patterns ◽

Validation Data ◽

Histone Marks

Chromatin-modifying enzymes mediate DNA methylation and histone modifications on recruitment to specific target gene loci in response to various stimuli. The key enzymes that regulate chromatin accessibility for maintenance of modifications in DNA and histones, and for modulation of gene expression patterns in response to cigarette smoke (CS), are not known. We hypothesize that CS exposure alters the gene expression patterns of chromatin-modifying enzymes, which then affects multiple downstream pathways involved in the response to CS. We have, therefore, analyzed chromatin-modifying enzyme profiles and validated by quantitative real-time PCR (qPCR). We also performed immunoblot analysis of targeted histone marks in C57BL/6J mice exposed to acute and subchronic CS, and of lungs from nonsmokers, smokers, and patients with chronic obstructive pulmonary disease (COPD). We found a significant increase in expression of several chromatin modification enzymes, including DNA methyltransferases, histone acetyltransferases, histone methyltransferases, and SET domain proteins, histone kinases, and ubiquitinases. Our qPCR validation data revealed a significant downregulation of Dnmt1, Dnmt3a, Dnmt3b, Hdac2, Hdac4, Hat1, Prmt1, and Aurkb. We identified targeted chromatin histone marks (H3K56ac and H4K12ac), which are induced by CS. Thus CS-induced genotoxic stress differentially affects the expression of epigenetic modulators that regulate transcription of target genes via DNA methylation and site-specific histone modifications. This may have implications in devising epigenetic-based therapies for COPD and lung cancer.

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The Progeny of Arabidopsis thaliana Plants Exposed to Salt Exhibit Changes in DNA Methylation, Histone Modifications and Gene Expression

PLoS ONE ◽

10.1371/journal.pone.0030515 ◽

2012 ◽

Vol 7 (1) ◽

pp. e30515 ◽

Cited By ~ 122

Author(s):

Andriy Bilichak ◽

Yaroslav Ilnystkyy ◽

Jens Hollunder ◽

Igor Kovalchuk

Keyword(s):

Gene Expression ◽

Dna Methylation ◽

Arabidopsis Thaliana ◽

Histone Modifications

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Epigenetic Variation Analysis Leads to Biomarker Discovery in Gastric Adenocarcinoma

Frontiers in Genetics ◽

10.3389/fgene.2020.551787 ◽

2020 ◽

Vol 11 ◽

Author(s):

Yan Zhang ◽

Dianjing Guo

Keyword(s):

Gene Expression ◽

Gastric Cancer ◽

Dna Methylation ◽

Gastric Adenocarcinoma ◽

Histone Modifications ◽

Biomarker Discovery ◽

Cancer Genome ◽

The Cancer Genome Atlas ◽

Integrated Analysis ◽

Epigenetic Variation

As one of the most common malignant tumors worldwide, gastric adenocarcinoma (GC) and its prognosis are still poorly understood. Various genetic and epigenetic factors have been indicated in GC carcinogenesis. However, a comprehensive and in-depth investigation of epigenetic alteration in gastric cancer is still missing. In this study, we systematically investigated some key epigenetic features in GC, including DNA methylation and five core histone modifications. Data from The Cancer Genome Atlas Program and other studies (Gene Expression Omnibus) were collected, analyzed, and validated with multivariate statistical analysis methods. The landscape of epi-modifications in gastric cancer was described. Chromatin state transition analysis showed a histone marker shift in gastric cancer genome by employing a Hidden-Markov-Model based approach, indicated that histone marks tend to label different sets of genes in GC compared to control. An additive effect of these epigenetic marks was observed by integrated analysis with gene expression data, suggesting epigenetic modifications may cooperatively regulate gene expression. However, the effect of DNA methylation was found more significant without the presence of the five histone modifications in our study. By constructing a PPI network, key genes to distinguish GC from normal samples were identified, and distinct patterns of oncogenic pathways in GC were revealed. Some of these genes can also serve as potential biomarkers to classify various GC molecular subtypes. Our results provide important insights into the epigenetic regulation in gastric cancer and other cancers in general. This study describes the aberrant epigenetic variation pattern in GC and provides potential direction for epigenetic biomarker discovery.

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The Use of Natural Products of Epigenetic Modulators in Anti-Cancer Drug Studies

Proceedings ◽

10.3390/proceedings2019040041 ◽

2019 ◽

Vol 40 (1) ◽

pp. 41

Author(s):

Demokan

Keyword(s):

Gene Expression ◽

Dna Methylation ◽

Natural Products ◽

Cancer Treatment ◽

Tumor Cells ◽

Histone Modifications ◽

Regulation Of Gene Expression ◽

Epigenetic Mechanisms ◽

Expression Of Genes ◽

Anti Cancer

The natural products obtained from plants, bacteria, fungi and marine have been used in the treatment of human diseases throughout the centuries. These compounds of them also interfere with the expression of genes by influencing epigenetic mechanisms. Recent researches showed significant outcomes suggesting that epigenetic silencing of the main regulatory genesis a sign of cancer onset and its progression. Epigenetic mechanisms that regulate expression of genes without mutation in the DNA are carried through DNA methylation, histone modification, chromatin remodeling and RNA interference. DNA methylation observed in the promoter regions of genes and prevents binding of the transcription factors by suppressing gene expression or by altering the nucleosome package of DNA, and may also directly inhibit transcription. Plant based products, such as curcumin, flavonoids, genistein, have been shown to exhibit cytostatic and apoptotic activities by influencing DNA methylation-based gene expression regulation in tumor cells. Additionally, natural products such as sulforaphane, retinoic acid, cucurbitacin B, casein Q, parthenolide, folate, cobalamin, pyridoxine and methionine also are used as anti-cancer agents based on DNA methylation. On the other hand, microRNAs (miRNAs) play a particular role in the epigenetic regulation of gene expression in post-transcription and post-translation processes. Quercetin, tryptolide, and honokiol are the natural compounds used in miRNA based agents. Histone modifications, which also affect the chromatin structure, play an important role in the initiation and progression of carcinogenesis as well as regulation of gene expression. As expected particular inhibitors of histone acetyltransferases (HATs) and histone deacetylase (HDAC) enzymes which are responsible of histone modifications have been developed for epigenetic intervention in cancer treatment. Numerous natural compounds are known to affect histone-modifying enzymes; such as romidepsin, epigallocatechingallate (EGCG), daidzein, sulphorafane, glucoraphanin, parthenolide, triptolide, sinapinic acid. Natural epigenetic modulators developed for epigenetic mechanisms enable the destruction of apoptotic, necrotic or autophagic pathways of tumor cells. Beside epigenetic mechanisms, these products exert their effects through influencing the cell cycle, DNA repair, and epigenetic mechanisms which modulate gene expression. More extensive in vitro and in vivo studies are required to investigate the effect of natural product-based epigenetic agents which seems to be very promising for future cancer treatment approaches.

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KRAB-Induced Heterochromatin Effectively Silences PLOD2 Gene Expression in Somatic Cells and Is Resilient to TGFβ1 Activation

International Journal of Molecular Sciences ◽

10.3390/ijms21103634 ◽

2020 ◽

Vol 21 (10) ◽

pp. 3634

Author(s):

Rutger A. F. Gjaltema ◽

Désirée Goubert ◽

Christian Huisman ◽

Consuelo del Pilar García Tobilla ◽

Mihály Koncz ◽

...

Keyword(s):

Gene Expression ◽

Dna Methylation ◽

Histone Modifications ◽

Mammalian Cells ◽

Dna Methyltransferase ◽

De Novo ◽

Context Dependency ◽

Dependent Manner ◽

In Vivo Models ◽

Epigenetic Editing

Epigenetic editing, an emerging technique used for the modulation of gene expression in mammalian cells, is a promising strategy to correct disease-related gene expression. Although epigenetic reprogramming results in sustained transcriptional modulation in several in vivo models, further studies are needed to develop this approach into a straightforward technology for effective and specific interventions. Important goals of current research efforts are understanding the context-dependency of successful epigenetic editing and finding the most effective epigenetic effector(s) for specific tasks. Here we tested whether the fibrosis- and cancer-associated PLOD2 gene can be repressed by the DNA methyltransferase M.SssI, or by the non-catalytic Krüppel associated box (KRAB) repressor directed to the PLOD2 promoter via zinc finger- or CRISPR-dCas9-mediated targeting. M.SssI fusions induced de novo DNA methylation, changed histone modifications in a context-dependent manner, and led to 50%–70% reduction in PLOD2 expression in fibrotic fibroblasts and in MDA-MB-231 cancer cells. Targeting KRAB to PLOD2 resulted in the deposition of repressive histone modifications without DNA methylation and in almost complete PLOD2 silencing. Interestingly, both long-term TGFβ1-induced, as well as unstimulated PLOD2 expression, was completely repressed by KRAB, while M.SssI only prevented the TGFβ1-induced PLOD2 expression. Targeting transiently expressed dCas9-KRAB resulted in sustained PLOD2 repression in HEK293T and MCF-7 cells. Together, these findings point to KRAB outperforming DNA methylation as a small potent targeting epigenetic effector for silencing TGFβ1-induced and uninduced PLOD2 expression.

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Characterization of histone modifications associated with DNA damage repair genes upon exposure to gamma rays in Arabidopsis seedlings

Journal of Radiation Research ◽

10.1093/jrr/rrw077 ◽

2016 ◽

Vol 57 (6) ◽

pp. 646-654 ◽

Cited By ~ 9

Author(s):

Suvendu Mondal ◽

Young Sam Go ◽

Seung Sik Lee ◽

Byung Yeoup Chung ◽

Jin-Hong Kim

Keyword(s):

Gene Expression ◽

Dna Methylation ◽

Gamma Irradiation ◽

Histone Modifications ◽

Gamma Rays ◽

Regulation Of Gene Expression ◽

Chromatin Modification ◽

Histone H3 ◽

Marker Genes ◽

Transcription Start Sites

Abstract Dynamic histone modifications play an important role in controlling gene expression in response to various environmental cues. This mechanism of regulation of gene expression is important for sessile organisms, like land plants. We have previously reported consistent upregulation of various marker genes in response to gamma rays at various post-irradiation times. In the present study, we performed various chromatin modification analyses at selected loci using the standard chromatin immunoprecipitation procedure, and demonstrate that upregulation of these genes is associated with histone H3 lysine 4 tri-methylation (H3K4me3) at the gene body or transcription start sites of these loci. Further, at specific AtAgo2 loci, both H3K4me3 and histone H3 lysine 9 acetylation (H3K9ac) are important in controlling gene expression in response to gamma irradiation. There was no change in DNA methylation in these selected loci. We conclude that specific histone modification such as H3K4me3 and H3K9ac may be more important in activating gene expression in these selected loci in response to gamma irradiation than a change in DNA methylation.

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Differences in global DNA methylation of testicular seminoma are not associated with changes in histone modifications, clinical prognosis, BRAF mutations or gene expression

Cancer Genetics ◽

10.1016/j.cancergen.2016.10.003 ◽

2016 ◽

Vol 209 (11) ◽

pp. 506-514 ◽

Cited By ~ 7

Author(s):

Louise Holm Pedersen ◽

John E. Nielsen ◽

Gedske Daugaard ◽

Thomas v.O. Hansen ◽

Ewa Rajpert-De Meyts ◽

...

Keyword(s):

Gene Expression ◽

Dna Methylation ◽

Histone Modifications ◽

Global Dna Methylation ◽

Braf Mutations ◽

Testicular Seminoma ◽

Clinical Prognosis ◽

Or Gene

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Integrated Epigenome Profiling of Repressive Histone Modifications, DNA Methylation and Gene Expression in Normal and Malignant Urothelial Cells

PLoS ONE ◽

10.1371/journal.pone.0032750 ◽

2012 ◽

Vol 7 (3) ◽

pp. e32750 ◽

Cited By ~ 25

Author(s):

Ewa Dudziec ◽

Andreas Gogol-Döring ◽

Victoria Cookson ◽

Wei Chen ◽

James Catto

Keyword(s):

Gene Expression ◽

Dna Methylation ◽

Histone Modifications ◽

Urothelial Cells

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Methylation QTLs are associated with coordinated changes in transcription factor binding, histone modifications, and gene expression levels

10.1101/006171 ◽

2014 ◽

Cited By ~ 1

Author(s):

Nicholas E. Banovich ◽

Xun Lan ◽

Graham McVicker ◽

Bryce van de Geijn ◽

Jacob F. Degner ◽

...

Keyword(s):

Gene Expression ◽

Dna Methylation ◽

Transcription Factor ◽

Genetic Variation ◽

Histone Modifications ◽

Transcription Factor Binding ◽

Dnase I ◽

Expression Levels ◽

Factor Binding ◽

Quantitative Changes

AbstractDNA methylation is an important epigenetic regulator of gene expression. Recent studies have revealed widespread associations between genetic variation and methylation levels. However, the mechanistic links between genetic variation and methylation remain unclear. To begin addressing this gap, we collected methylation data at ∼300,000 loci in lymphoblastoid cell lines (LCLs) from 64 HapMap Yoruba individuals, and genome-wide bisulfite sequence data in ten of these individuals. We identified (at an FDR of 10%) 13,915 cis methylation QTLs (meQTLs)—i.e., CpG sites in which changes in DNA methylation are associated with genetic variation at proximal loci. We found that meQTLs are frequently associated with changes in methylation at multiple CpGs across regions of up to 3 kb. Interestingly, meQTLs are also frequently associated with variation in other properties of gene regulation, including histone modifications, DNase I accessibility, chromatin accessibility, and expression levels of nearby genes. These observations suggest that genetic variants may lead to coordinated molecular changes in all of these regulatory phenotypes. One plausible driver of coordinated changes in different regulatory mechanisms is variation in transcription factor (TF) binding. Indeed, we found that SNPs that change predicted TF binding affinities are significantly enriched for associations with DNA methylation at nearby CpGs.Author SummaryDNA methylation is an important epigenetic mark that contributes to many biological processes including the regulation of gene expression. Genetic variation has been associated with quantitative changes in DNA methylation (meQTLs). We identified thousands of meQTLs using an assay that allowed us to measure methylation levels at around 300 thousand cytosines. We found that meQTLs are enriched with loci that is also associated with quantitative changes in gene expression, DNase I hypersensitivity, PolII occupancy, and a number of histone marks. This suggests that many molecular events are likely regulated in concert. Finally, we found that changes in transcription factor binding as well as transcription factor abundance are associated with changes in DNA methylation near transcription factor binding sites. This work contributes to our understanding of the regulation of DNA methylation in the larger context of gene regulatory landscape.

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