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 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 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 GSDMA drives the most replicated association with asthma in naïve CD4+ T cells

2019 ◽  
Author(s):  
Anne-Marie Madore ◽  
Lucile Pain ◽  
Anne-Marie Boucher-Lafleur ◽  
Jolyane Meloche ◽  
Andréanne Morin ◽  
...  
Keyword(s):  
Gene Expression ◽  
Dna Methylation ◽  
T Cells ◽  
Genetic Variants ◽  
Immune Cell ◽  
Cell Types ◽  
Sequencing Data ◽  
Opposite Pattern ◽  
Genetic Mechanisms ◽  
New Gene

AbstractBackgroundThe 17q12-21 locus is the most replicated association with asthma. However, no study had described the genetic mechanisms underlying this association considering all genes of the locus in immune cell samples isolated from asthmatic and non-asthmatic individuals.ObjectiveThis study takes benefit of samples from naïve CD4+ T cells and eosinophils isolated from the same 200 individuals to describe specific interactions between genetic variants, gene expression and DNA methylation levels for the 17q12-21 asthma locus.Methods and ResultsAfter isolation of naïve CD4+ T cells and eosinophils from blood samples, next generation sequencing was used to measure DNA methylation levels and gene expression counts. Genetic interactions were then evaluated considering genetic variants from imputed genotype data. In naïve CD4+ T cells but not eosinophils, 20 SNPs in the fourth and fifth haplotype blocks modulated both GSDMA expression and methylation levels, showing an opposite pattern of allele frequencies and expression counts in asthmatics compared to controls. Moreover, negative correlations have been measured between methylation levels of CpG sites located within the 1.5 kb region from the transcription start site of GSDMA and its expression counts.ConclusionAvailability of sequencing data from two key cell types isolated from asthmatic and non-asthmatic individuals allowed identifying a new gene in naïve CD4+ T cells that drives the association with the 17q12-21 locus, leading to a better understanding of the genetic mechanisms taking place in it.

Abstract 18584: Decoding the Regulatory LncRNAs in Neonatal Heart During Perinatal Circulatory Transition

Circulation ◽  
2015 ◽  
Vol 132 (suppl_3) ◽  
Author(s):  
Marlin Touma ◽  
Ashley Cass ◽  
Xuedong Kang ◽  
Yan Zhao ◽  
Reshma Biniwale ◽  
...  
Keyword(s):  
Gene Expression ◽  
Cell Cycle ◽  
Rna Sequencing ◽  
Expression Patterns ◽  
Regulatory Function ◽  
Newborn Mouse ◽  
Protein Coding ◽  
Congenital Diseases ◽  
Gene Pairs ◽  
Neonatal Heart

Background: Fetal to neonatal transition of heart is an elaborate process, during which, neonatal cardiomyocytes undergo functional maturation and terminal exit from the cell cycle. However, transcriptome programming in neonatal cardiac chambers during perinatal stages is understudied. In particular, the changes in long non-coding RNAs (lncRNAs) in neonatal heart have not been explored. Objective: To achieve transcriptome-wide analysis of lncRNAs in neonatal left ventricle (LV) and right ventricle (RV) during maturation stages using deep RNA-Sequencing Methods: Deep RNA-sequencing was performed on male newborn mouse (C57 BL) LV and RV at 3 time points of perinatal circulatory transition: P0, P3 and P7. Reads were mapped to mouse genome (mm10). The lncRNAs annotated in NONCODE database were identified. Differentially expressed lncRNAs were defined as those with coefficient of variation ≥0.2, at a false discovery rate ≤0.05, and expressed at ≥3 RPKM in at least one sample. Correlated lncRNAs/ gene pairs were identified using Pearson’s (r2≥0.8, P≤0.05). A subset of LncRNAs/gene expression was validated using qRT-PCR. Results: Out of the 70, 983 observed unique lncRNAs, approximately 7000 were identified exhibiting significant variation during maturation windows with highly spatial-temporal dependent expression patterns, including approximately 5000 known and 2000 novel lncRNAs. Notably, 20% of these lncRNAs were located within 50 KB of a protein coding gene. Out of a total of 2400 lncRNAs/gene pairs, 10 % exhibited significantly concordant (lncRNA/gene) expression patterns. These correlated genes were significantly enriched in metabolism, cell cycle and contractility functional ontology. Interestingly, some of these lncRNAs exhibited concordance with their neighboring gene in human tissues with congenital heart defects, suggesting conserved, potentially significant, regulatory function. Conclusions: Transcriptome programming during neonatal heart maturation involves global changes in lncRNAs. Their expression concordance with neighboring protein coding genes implicates potential important regulatory role of lncRNAs in neonatal heart chamber specification and congenital diseases.

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 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 A Genome-Wide mQTL Analysis in Human Adipose Tissue Identifies Genetic Variants Associated with DNA Methylation, Gene Expression and Metabolic Traits

PLoS ONE ◽  
2016 ◽  
Vol 11 (6) ◽  
pp. e0157776 ◽  
Author(s):  
Petr Volkov ◽  
Anders H. Olsson ◽  
Linn Gillberg ◽  
Sine W. Jørgensen ◽  
Charlotte Brøns ◽  
...  
Keyword(s):  
Gene Expression ◽  
Dna Methylation ◽  
Adipose Tissue ◽  
Genetic Variants ◽  
Human Adipose Tissue ◽  
Metabolic Traits ◽  
Genome Wide ◽  
A Genome

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 Leveraging brain cortex-derived molecular data to elucidate epigenetic and transcriptomic drivers of neurological function and disease

2018 ◽  
Author(s):  
Charlie Hatcher ◽  
Caroline L. Relton ◽  
Tom R. Gaunt ◽  
Tom G. Richardson
Keyword(s):  
Gene Expression ◽  
Dna Methylation ◽  
Histone Acetylation ◽  
Genetic Variants ◽  
Large Scale ◽  
Genetic Variant ◽  
Association Studies ◽  
Genome Wide Association Studies ◽  
Epigenetic Mechanisms ◽  
Trait Variation

AbstractIntegrative approaches which harness large-scale molecular datasets can help develop mechanistic insight into findings from genome-wide association studies (GWAS). We have performed extensive analyses to uncover transcriptional and epigenetic processes which may play a role in neurological trait variation.This was undertaken by applying Bayesian multiple-trait colocalization systematically across the genome to identify genetic variants responsible for influencing intermediate molecular phenotypes as well as neurological traits. In this analysis we leveraged high dimensional quantitative trait loci data derived from prefrontal cortex tissue (concerning gene expression, DNA methylation and histone acetylation) and GWAS findings for 5 neurological traits (Neuroticism, Schizophrenia, Educational Attainment, Insomnia and Alzheimer’s disease).There was evidence of colocalization for 118 associations suggesting that the same underlying genetic variant influenced both nearby gene expression as well as neurological trait variation. Of these, 73 associations provided evidence that the genetic variant also influenced proximal DNA methylation and/or histone acetylation. These findings support previous evidence at loci where epigenetic mechanisms may putatively mediate effects of genetic variants on traits, such as KLC1 and schizophrenia. We also uncovered evidence implicating novel loci in neurological disease susceptibility, including genes expressed predominantly in brain tissue such as MDGA1, KIRREL3 and SLC12A5.An inverse relationship between DNA methylation and gene expression was observed more than can be accounted for by chance, supporting previous findings implicating DNA methylation as a transcriptional repressor. Our study should prove valuable in helping future studies prioritise candidate genes and epigenetic mechanisms for in-depth functional follow-up analyses.

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