scholarly journals Dioxin Disrupts Dynamic DNA Methylation Patterns in Genes That Govern Cardiomyocyte Maturation

2020 ◽  
Vol 178 (2) ◽  
pp. 325-337
Author(s):  
Matthew de Gannes ◽  
Chia-I Ko ◽  
Xiang Zhang ◽  
Jacek Biesiada ◽  
Liang Niu ◽  
...  
Keyword(s):  
Gene Expression ◽  
Dna Methylation ◽  
Heart Development ◽  
Expression Patterns ◽  
Embryonic Stem Cell Line ◽  
Molecular Networks ◽  
Unknown Etiology ◽  
Postnatal Maturation ◽  
Complex Interactions ◽  
And Function

Abstract Congenital heart disease (CHD), the leading birth defect worldwide, has a largely unknown etiology, likely to result from complex interactions between genetic and environmental factors during heart development, at a time when the heart adapts to diverse physiological and pathophysiological conditions. Crucial among these is the regulation of cardiomyocyte development and postnatal maturation, governed by dynamic changes in DNA methylation. Previous work from our laboratory has shown that exposure to the environmental toxicant tetrachlorodibenzo-p-dioxin (TCDD) disrupts several molecular networks responsible for heart development and function. To test the hypothesis that the disruption caused by TCDD in the heart results from changes in DNA methylation and gene expression patterns of cardiomyocytes, we established a stable mouse embryonic stem cell line expressing a puromycin resistance selectable marker under control of the cardiomyocyte-specific Nkx2-5 promoter. Differentiation of these cells in the presence of puromycin induces the expression of a large suite of cardiomyocyte-specific markers. To assess the consequences of TCDD treatment on gene expression and DNA methylation in these cardiomyocytes, we subjected them to transcriptome and methylome analyses in the presence of TCDD. Unlike control cardiomyocytes maintained in vehicle, the TCDD-treated cardiomyocytes showed extensive gene expression changes, with a significant correlation between differential RNA expression and DNA methylation in 111 genes, many of which are key elements of pathways that regulate cardiovascular development and function. Our findings provide an important clue toward the elucidation of the complex interactions between genetic and epigenetic mechanisms after developmental TCDD exposure that may contribute to CHD.

scholarly journals On the origin and evolutionary consequences of gene body DNA methylation

2016 ◽  
Vol 113 (32) ◽  
pp. 9111-9116 ◽  
Author(s):  
Adam J. Bewick ◽  
Lexiang Ji ◽  
Chad E. Niederhuth ◽  
Eva-Maria Willing ◽  
Brigitte T. Hofmeister ◽  
...  
Keyword(s):  
Gene Expression ◽  
Dna Methylation ◽  
Recombinant Inbred Lines ◽  
Dna Methyltransferases ◽  
Inbred Lines ◽  
Gene Body ◽  
Gene Body Methylation ◽  
Eutrema Salsugineum ◽  
And Function ◽  
Evolutionary Consequences

In plants, CG DNA methylation is prevalent in the transcribed regions of many constitutively expressed genes (gene body methylation; gbM), but the origin and function of gbM remain unknown. Here we report the discovery that Eutrema salsugineum has lost gbM from its genome, to our knowledge the first instance for an angiosperm. Of all known DNA methyltransferases, only CHROMOMETHYLASE 3 (CMT3) is missing from E. salsugineum. Identification of an additional angiosperm, Conringia planisiliqua, which independently lost CMT3 and gbM, supports that CMT3 is required for the establishment of gbM. Detailed analyses of gene expression, the histone variant H2A.Z, and various histone modifications in E. salsugineum and in Arabidopsis thaliana epigenetic recombinant inbred lines found no evidence in support of any role for gbM in regulating transcription or affecting the composition and modification of chromatin over evolutionary timescales.

Abstract 290: Proliferation of Cardiac Fibroblasts Defines Early Stages of Genetic Dilated Cardiomyopathy and Precedes Myocardial Metabolic Derangement

2014 ◽  
Vol 115 (suppl_1) ◽  
Author(s):  
Michael A Burke ◽  
Stephen Chang ◽  
Danos C Christodoulou ◽  
Joshua M Gorham ◽  
Hiroko Wakimoto ◽  
...  
Keyword(s):  
Gene Expression ◽  
Cardiac Fibroblasts ◽  
Expression Patterns ◽  
Molecular Networks ◽  
Peroxisome Proliferator ◽  
Metabolic Derangement ◽  
Peroxisome Proliferator Activated Receptor ◽  
Cell Remodeling ◽  
Ppar Signaling ◽  
Myocyte Proliferation

The complex molecular networks underpinning DCM remain poorly understood. To study distinct pathways and networks in the longitudinal development of DCM we performed RNAseq on LV tissue from mice carrying a human DCM mutation in phospholamban (PLN R9C/+ ) before phenotype onset (pre-DCM), with DCM, and during overt heart failure (HF), and also on isolated myocytes and non-myocytes from DCM hearts. PLN R9C/+ mice show progressive fibrosis (20% vs. 1% control, p=6x10 −33 ; n=3) associated with proliferation of cardiac non-myocytes (33% increase over control, p=6x10 −4 ; n=3). Consistent with this, cardiac non-myocytes have upregulated gene expression and pathways, while these are generally downregulated in myocytes. Non-myocytes were enriched in fibrosis, inflammation, and cell remodeling pathways, from pre-DCM to HF. In contrast, myocytes were enriched for metabolic pathways only with overt DCM and HF. Myocytes showed profound derangement of oxidative phosphorylation with DCM (p=2.5x10 −41 ; 44% (53/120) of pathway genes downregulated), suggesting mitochondrial dysfunction. Additionally, we detected probable inhibition of peroxisome proliferator-activated receptor (PPAR) signaling by diminished expression of pathway genes (Figure). DCM and hypertrophic remodeling was compared using RNAseq of a mouse model of HCM; similar patterns of fibrosis with myocyte metabolic dysregulation were evident despite unique differential gene expression patterns between models. DCM caused by PLN R9C/+ is associated with early non-myocyte proliferation and later myocyte metabolic derangement possibly governed by altered PPAR signaling, and is common to DCM and HCM.

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

2016 ◽  
Vol 311 (6) ◽  
pp. L1245-L1258 ◽  
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.

scholarly journals An integrative multi-omics approach in Sjögren’s Syndrome identifies novel genetic drivers with regulatory function and disease-specificity

2020 ◽  
Author(s):  
María Teruel ◽  
Guillermo Barturen ◽  
Manuel Martínez-Bueno ◽  
Miguel Barroso ◽  
Olivia Castelli ◽  
...  
Keyword(s):  
Gene Expression ◽  
Dna Methylation ◽  
Sjögren’S Syndrome ◽  
Genetic Variants ◽  
Sjögren's Syndrome ◽  
Expression Patterns ◽  
Sjogren’S Syndrome ◽  
Sjogren's Syndrome ◽  
Regulatory Function ◽  
Sjögren‘S Syndrome

ABSTRACTPrimary Sjögren’s syndrome (SS) is a systemic autoimmune disease characterized by lymphocytic infiltration and damage of exocrine salivary and lacrimal glands. The etiology of SS is complex with environmental triggers and genetic factors involved. By conducting an integrated multi-omics study we identified vast coordinated hypomethylation and overexpression effects, that also exhibit increased variability, in many already known IFN-regulated genes. We report a novel epigenetic signature characterized by increased DNA methylation levels in a large number of novel genes enriched in pathways such as collagen metabolism and extracellular matrix organization. We identified new genetic variants associated with SS that mediate their risk by altering DNA methylation or gene expression patterns, as well as disease-interacting genetic variants that exhibit regulatory function only in the SS population. Our study sheds new light on the interaction between genetics, DNA methylation, gene expression and SS, and contributes to elucidate the genetic architecture of gene regulation in an autoimmune population.

scholarly journals Maternal and Post-weaning High-Fat Diets Produce Distinct DNA Methylation Patterns in Hepatic Metabolic Pathways within Specific Genomic Contexts

2019 ◽  
Vol 20 (13) ◽  
pp. 3229 ◽  
Author(s):  
Moody ◽  
Wang ◽  
Jung ◽  
Chen ◽  
Pan
Keyword(s):  
Gene Expression ◽  
Dna Methylation ◽  
Metabolic Pathways ◽  
Expression Patterns ◽  
Sprague Dawley ◽  
High Fat ◽  
Differentially Methylated Genes ◽  
High Fat Diets ◽  
Diet Intake ◽  
Fat Diets

Calorie-dense high-fat diets (HF) are associated with detrimental health outcomes, including obesity, cardiovascular disease, and diabetes. Both pre- and post-natal HF diets have been hypothesized to negatively impact long-term metabolic health via epigenetic mechanisms. To understand how the timing of HF diet intake impacts DNA methylation and metabolism, male Sprague–Dawley rats were exposed to either maternal HF (MHF) or post-weaning HF diet (PHF). At post-natal week 12, PHF rats had similar body weights but greater hepatic lipid accumulation compared to the MHF rats. Genome-wide DNA methylation was evaluated, and analysis revealed 1744 differentially methylation regions (DMRs) between the groups with the majority of the DMR located outside of gene-coding regions. Within differentially methylated genes (DMGs), intragenic DNA methylation closer to the transcription start site was associated with lower gene expression, whereas DNA methylation further downstream was positively correlated with gene expression. The insulin and phosphatidylinositol (PI) signaling pathways were enriched with 25 DMRs that were associated with 20 DMGs, including PI3 kinase (Pi3k), pyruvate kinase (Pklr), and phosphodiesterase 3 (Pde3). Together, these results suggest that the timing of HF diet intake determines DNA methylation and gene expression patterns in hepatic metabolic pathways that target specific genomic contexts.

scholarly journals Impact of Transposable Elements on Methylation and Gene Expression across Natural Accessions of Brachypodium distachyon

2020 ◽  
Vol 12 (11) ◽  
pp. 1994-2001 ◽  
Author(s):  
Michele Wyler ◽  
Christoph Stritt ◽  
Jean-Claude Walser ◽  
Célia Baroux ◽  
Anne C Roulin
Keyword(s):  
Gene Expression ◽  
Dna Methylation ◽  
Transposable Elements ◽  
Brachypodium Distachyon ◽  
Large Fraction ◽  
Expression Patterns ◽  
Specific Gene ◽  
Differential Gene ◽  
The Relationship ◽  
Silent State

Abstract Transposable elements (TEs) constitute a large fraction of plant genomes and are mostly present in a transcriptionally silent state through repressive epigenetic modifications, such as DNA methylation. TE silencing is believed to influence the regulation of adjacent genes, possibly as DNA methylation spreads away from the TE. Whether this is a general principle or a context-dependent phenomenon is still under debate, pressing for studying the relationship between TEs, DNA methylation, and nearby gene expression in additional plant species. Here, we used the grass Brachypodium distachyon as a model and produced DNA methylation and transcriptome profiles for 11 natural accessions. In contrast to what is observed in Arabidopsis thaliana, we found that TEs have a limited impact on methylation spreading and that only few TE families are associated with a low expression of their adjacent genes. Interestingly, we found that a subset of TE insertion polymorphisms is associated with differential gene expression across accessions. Thus, although not having a global impact on gene expression, distinct TE insertions may contribute to specific gene expression patterns in B. distachyon.

scholarly journals CG gene body DNA methylation changes and evolution of duplicated genes in cassava

2015 ◽  
Vol 112 (44) ◽  
pp. 13729-13734 ◽  
Author(s):  
Haifeng Wang ◽  
Getu Beyene ◽  
Jixian Zhai ◽  
Suhua Feng ◽  
Noah Fahlgren ◽  
...  
Keyword(s):  
Gene Expression ◽  
Dna Methylation ◽  
Expression Patterns ◽  
Regulation Of Gene Expression ◽  
Gene Copy ◽  
Gene Body ◽  
Duplicated Genes ◽  
Gene Body Methylation ◽  
Substantial Impact ◽  
Tropical Regions

DNA methylation is important for the regulation of gene expression and the silencing of transposons in plants. Here we present genome-wide methylation patterns at single-base pair resolution for cassava (Manihot esculenta, cultivar TME 7), a crop with a substantial impact in the agriculture of subtropical and tropical regions. On average, DNA methylation levels were higher in all three DNA sequence contexts (CG, CHG, and CHH, where H equals A, T, or C) than those of the most well-studied model plant Arabidopsis thaliana. As in other plants, DNA methylation was found both on transposons and in the transcribed regions (bodies) of many genes. Consistent with these patterns, at least one cassava gene copy of all of the known components of Arabidopsis DNA methylation pathways was identified. Methylation of LTR transposons (GYPSY and COPIA) was found to be unusually high compared with other types of transposons, suggesting that the control of the activity of these two types of transposons may be especially important. Analysis of duplicated gene pairs resulting from whole-genome duplication showed that gene body DNA methylation and gene expression levels have coevolved over short evolutionary time scales, reinforcing the positive relationship between gene body methylation and high levels of gene expression. Duplicated genes with the most divergent gene body methylation and expression patterns were found to have distinct biological functions and may have been under natural or human selection for cassava traits.

scholarly journals Identification and Characterization of Key Differentially Expressed Genes Associated With Metronomic Dosing of Topotecan in Human Prostate Cancer

2021 ◽  
Vol 12 ◽  
Author(s):  
Taraswi Mitra Ghosh ◽  
Jason White ◽  
Joshua Davis ◽  
Suman Mazumder ◽  
Teeratas Kansom ◽  
...  
Keyword(s):  
Gene Expression ◽  
Prostate Cancer ◽  
Cell Lines ◽  
Differentially Expressed Genes ◽  
Expression Patterns ◽  
Differentially Expressed ◽  
Molecular Networks ◽  
Human Prostate ◽  
Mouse Tumor ◽  
Human Prostate Cancer

Repetitive, low-dose (metronomic; METRO) drug administration of some anticancer agents can overcome drug resistance and increase drug efficacy in many cancers, but the mechanisms are not understood fully. Previously, we showed that METRO dosing of topotecan (TOPO) is more effective than conventional (CONV) dosing in aggressive human prostate cancer (PCa) cell lines and in mouse tumor xenograft models. To gain mechanistic insights into METRO-TOPO activity, in this study we determined the effect of METRO- and CONV-TOPO treatment in a panel of human PCa cell lines representing castration-sensitive/resistant, androgen receptor (+/−), and those of different ethnicity on cell growth and gene expression. Differentially expressed genes (DEGs) were identified for METRO-TOPO therapy and compared to a PCa patient cohort and The Cancer Genome Atlas (TCGA) database. The top five DEGs were SERPINB5, CDKN1A, TNF, FOS, and ANGPT1. Ingenuity Pathway Analysis predicted several upstream regulators and identified top molecular networks associated with METRO dosing, including tumor suppression, anti-proliferation, angiogenesis, invasion, metastasis, and inflammation. Further, the top DEGs were associated with increase survival of PCa patients (TCGA database), as well as ethnic differences in gene expression patterns in patients and cell lines representing African Americans (AA) and European Americans (EA). Thus, we have identified candidate pharmacogenomic biomarkers and novel pathways associated with METRO-TOPO therapy that will serve as a foundation for further investigation and validation of METRO-TOPO as a novel treatment option for prostate cancers.

scholarly journals Integrative epigenomics in Sjögren´s syndrome reveals novel pathways and a strong interaction between the HLA, autoantibodies and the interferon signature

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
María Teruel ◽  
Guillermo Barturen ◽  
Manuel Martínez-Bueno ◽  
Olivia Castellini-Pérez ◽  
Miguel Barroso-Gil ◽  
...  
Keyword(s):  
Gene Expression ◽  
Dna Methylation ◽  
Strong Interaction ◽  
Genetic Variants ◽  
Expression Patterns ◽  
Lymphocytic Infiltration ◽  
Regulatory Function ◽  
Systemic Autoimmune Disease ◽  
Matrix Organization ◽  
Or Gene

AbstractPrimary Sjögren’s syndrome (SS) is a systemic autoimmune disease characterized by lymphocytic infiltration and damage of exocrine salivary and lacrimal glands. The etiology of SS is complex with environmental triggers and genetic factors involved. By conducting an integrated multi-omics study, we confirmed a vast coordinated hypomethylation and overexpression effects in IFN-related genes, what is known as the IFN signature. Stratified and conditional analyses suggest a strong interaction between SS-associated HLA genetic variation and the presence of Anti-Ro/SSA autoantibodies in driving the IFN epigenetic signature and determining SS. We report a novel epigenetic signature characterized by increased DNA methylation levels in a large number of genes enriched in pathways such as collagen metabolism and extracellular matrix organization. We identified potential new genetic variants associated with SS that might mediate their risk by altering DNA methylation or gene expression patterns, as well as disease-interacting genetic variants that exhibit regulatory function only in the SS population. Our study sheds new light on the interaction between genetics, autoantibody profiles, DNA methylation and gene expression in SS, and contributes to elucidate the genetic architecture of gene regulation in an autoimmune population.

scholarly journals Impact of transposable elements on methylation and gene expression across natural accessions of Brachypodium distachyon

2020 ◽  
Author(s):  
Michele Wyler ◽  
Christoph Stritt ◽  
Jean-Claude Walser ◽  
Célia Baroux ◽  
Anne C. Roulin
Keyword(s):  
Gene Expression ◽  
Dna Methylation ◽  
Transposable Elements ◽  
Plant Species ◽  
Brachypodium Distachyon ◽  
Expression Patterns ◽  
Small Subset ◽  
Molecular Evidence ◽  
Specific Gene ◽  
Plant Genomes

AbstractTransposable elements (TEs) constitute a large fraction of plant genomes and are mostly present in a transcriptionally silent state through repressive epigenetic modifications such as DNA methylation. TE silencing is believed to influence the regulation of adjacent genes, possibly as DNA methylation spreads away from the TE. Whether this is a general principle or a context-dependent phenomenon is still under debate, pressing for studying the relationship between TEs, DNA methylation and nearby gene expression in additional plant species. Here we used the grass Brachypodium distachyon as a model and produced DNA methylation and transcriptome profiles for eleven natural accessions. In contrast to what is observed in Arabidopsis thaliana, we found that TEs have a limited impact on methylation spreading and that only few TE families are associated to a low expression of their adjacent genes. Interestingly, we found that a subset of TE insertion polymorphisms is associated with differential gene expression across accessions. Thus, although not having a global impact on gene expression, distinct TE insertions may contribute to specific gene expression patterns in B. distachyon.Significance statementTransposable elements (TEs) are a major component of plant genomes and a source of genetic and epigenetic innovations underlying adaptation to changing environmental conditions. Yet molecular evidence linking TE silencing and nearby gene expression are lacking for many plant species. We show that in the model grass Brachypodium DNA methylation spreads over very short distances around TEs, with an influence on gene expression for a small subset of TE families.

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