scholarly journals CpG traffic lights are markers of regulatory regions in humans

2016 ◽  
Author(s):  
Abdullah M. Khamis ◽  
Anna V. Lioznova ◽  
Artem V. Artemov ◽  
Vasily Ramensky ◽  
Vladimir B. Bajic ◽  
...  
Keyword(s):  
Gene Expression ◽  
Dna Methylation ◽  
Regulation Of Gene Expression ◽  
Cell Types ◽  
Regulatory Elements ◽  
Cpg Methylation ◽  
Population Heterogeneity ◽  
Gene Body Methylation ◽  
Enhancer Activity ◽  
Traffic Lights

AbstractDNA methylation is involved in regulation of gene expression. Although modern methods profile DNA methylation at single CpG sites, methylation levels are usually averaged over genomic regions in the downstream analyses. In this study we demonstrate that single CpG methylation can serve as a more accurate predictor of gene expression compared to average promoter / gene body methylation. CpG positions with significant correlation between methylation and expression of a gene nearby (named CpG traffic lights) are evolutionary conserved and enriched for exact TSS positions and active enhancers. Among all promoter types, CpG traffic lights are especially enriched in poised promoters. Genes that harbor CpG traffic lights are associated with development and signal transduction. Methylation levels of individual CpG traffic lights vary between cell types dramatically with the increased frequency of intermediate methylation levels, indicating cell population heterogeneity in CpG methylation levels. Being in line with the concept of the inherited stochastic epigenetic variation, methylation of such CpG positions might contribute to transcriptional regulation. Alternatively, one can hypothesize that traffic lights are markers of absent gene expression resulting from inactivation of their regulatory elements. The CpG traffic lights provide a promising insight into mechanisms of enhancer activity and gene regulation linking methylation of single CpG to expression.

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 Identifying causal models between genetically regulated methylation patterns and gene expression in healthy colon tissue

2021 ◽  
Vol 13 (1) ◽  
Author(s):  
Anna Díez-Villanueva ◽  
Mireia Jordà ◽  
Robert Carreras-Torres ◽  
Henar Alonso ◽  
David Cordero ◽  
...  
Keyword(s):  
Gene Expression ◽  
Dna Methylation ◽  
Quantitative Trait Loci ◽  
Genetic Variants ◽  
Quantitative Trait ◽  
Regulation Of Gene Expression ◽  
Regulatory Elements ◽  
Colon Tissue ◽  
Tissue Samples ◽  
Trait Loci

Abstract Background DNA methylation is involved in the regulation of gene expression and phenotypic variation, but the inter-relationship between genetic variation, DNA methylation and gene expression remains poorly understood. Here we combine the analysis of genetic variants related to methylation markers (methylation quantitative trait loci: mQTLs) and gene expression (expression quantitative trait loci: eQTLs) with methylation markers related to gene expression (expression quantitative trait methylation: eQTMs), to provide novel insights into the genetic/epigenetic architecture of colocalizing molecular markers. Results Normal mucosa from 100 patients with colon cancer and 50 healthy donors included in the Colonomics project have been analyzed. Linear models have been used to find mQTLs and eQTMs within 1 Mb of the target gene. From 32,446 eQTLs previously detected, we found a total of 6850 SNPs, 114 CpGs and 52 genes interrelated, generating 13,987 significant combinations of co-occurring associations (meQTLs) after Bonferromi correction. Non-redundant meQTLs were 54, enriched in genes involved in metabolism of glucose and xenobiotics and immune system. SNPs in meQTLs were enriched in regulatory elements (enhancers and promoters) compared to random SNPs within 1 Mb of genes. Three colorectal cancer GWAS SNPs were related to methylation changes, and four SNPs were related to chemerin levels. Bayesian networks have been used to identify putative causal relationships among associated SNPs, CpG and gene expression triads. We identified that most of these combinations showed the canonical pathway of methylation markers causes gene expression variation (60.1%) or non-causal relationship between methylation and gene expression (33.9%); however, in up to 6% of these combinations, gene expression was causing variation in methylation markers. Conclusions In this study we provided a characterization of the regulation between genetic variants and inter-dependent methylation markers and gene expression in a set of 150 healthy colon tissue samples. This is an important finding for the understanding of molecular susceptibility on colon-related complex diseases.

Analysis of DNA Methylation and Transcription During Granulopoiesis Reveals Timed Methylation Changes in Low CpG Areas That Correlate with Changed Transcriptional Activity.

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 2334-2334
Author(s):  
Rönnerblad Michelle ◽  
Olofsson Tor ◽  
Iyadh Douagi ◽  
Sören Lehmann ◽  
Karl Ekwall ◽  
...  
Keyword(s):  
Gene Expression ◽  
Dna Methylation ◽  
Conflicts Of Interest ◽  
Cell Types ◽  
Cpg Methylation ◽  
Epigenetic Mechanism ◽  
450K Array ◽  
Chi Square ◽  
Heterochromatin Formation ◽  
Chi Square Test

Abstract Abstract 2334 Accumulating evidence demonstrates that epigenetic changes, including DNA methylation play a central role in differentiation, providing cellular memory and stabilizing lineage choice in hematopoiesis1–3. DNA methylation is an important epigenetic mechanism involved in transcriptional regulation, heterochromatin formation and the normal development of many organisms. In this study we investigated the DNA methylome and transcriptome of human cells in four separate differentiation stages in granulopoiesis, ranging from the multipotent Common Myeloid progenitor (CMP) to terminally differentiated bone marrow neutrophils (PMN). To this end we employed HumanMethylation 450 BeadChip (450K array) from Illumina with extensive genomic coverage and mRNA expression arrays (Illumina). Temporally distinct methylation changes during granulopoiesis Differential methylation between two cell stages was defined as an average difference in β value of at least 0.17 (p ≤ 0.05). We detected 12132 DMSs during granulopoiesis. Of these the majority showed decreased methylation during granulopoeisis (10771 CpGs) and a smaller set gained methylation (1658 CpGs). Strikingly, increases in methylation predominantly occur between CMP and GMP, the two least mature cell types. Some CpGs also show increased methylation in the GMP-PMC transition, while very few CpG sites increase at the final stage of differentiation from PMC to PMN. Although reduction of methylation occurs at all stages of granulopoiesis, the greatest change is between GMP and PMC. It is striking that the DNA methylation patterns preferentially change at points of lineage restriction, and that the greatest change occurs upon loss of oligopotency between GMP and PMC. DMSs within CGIs were greatly underrepresented (p<0.001 with chi-square test), while DMSs were overrepresented in shelves (p<0.001) and open sea (p<0.001). Thus, methylation appears to be more dynamic outside of CGIs during granulocytic development. For all regions the variation within enhancers was greater than outside of enhancers indicating greater methylation changes in enhancers compared to non-enhancers. In addition, CpGs in enhancer regions are significantly enriched in the list of DMSs (p<0.001, chi-square test) further supporting the observation that enhancer regions display dynamic DNA methylation changes during granulopoiesis. Changes in gene expression correlate with DNA methylation changes There was a significant overlap between genes showing decreased methylation and genes with increased expression as well as for the reverse comparison between genes with increased methylation and decreased expression. Thus, support a general anticorrelation between DNA methylation and gene expression. Azurophilic granule proteins showed increased expression peaking in PMC and a rapid decrease toward PMN. CpG methylation levels for those genes decreased concomitantly with the peak in expression. We report cell population specific changes of DNA methylation levels. The main reduction of CpG methylation coincides with the loss of oligopotency at the transition from GMP-PMC. This suggests a role of DNA methylation in regulating cell plasticity and lineage choice. Disclosures: No relevant conflicts of interest to declare.

scholarly journals GATA-1 Modulates the Chromatin Structure and Activity of the Chicken α-Globin 3′ Enhancer

2007 ◽  
Vol 28 (2) ◽  
pp. 575-586 ◽  
Author(s):  
Martín Escamilla-Del-Arenal ◽  
Félix Recillas-Targa
Keyword(s):  
Gene Expression ◽  
Chromatin Structure ◽  
Globin Gene ◽  
Regulation Of Gene Expression ◽  
Erythroid Differentiation ◽  
Regulatory Elements ◽  
Long Distance ◽  
Enhancer Activity ◽  
Free Region ◽  
Hypersensitive Sites

ABSTRACT Long-distance regulatory elements and local chromatin structure are critical for proper regulation of gene expression. Here we characterize the chromatin conformation of the chicken α-globin silencer-enhancer elements located 3′ of the domain. We found a characteristic and erythrocyte-specific structure between the previously defined silencer and the enhancer, defined by two nuclease hypersensitive sites, which appear when the enhancer is active during erythroid differentiation. Fine mapping of these sites demonstrates the absence of a positioned nucleosome and the association of GATA-1. Functional analyses of episomal vectors, as well as stably integrated constructs, revealed that GATA-1 plays a major role in defining both the chromatin structure and the enhancer activity. We detected a progressive enrichment of histone acetylation on critical enhancer nuclear factor binding sites, in correlation with the formation of an apparent nucleosome-free region. On the basis of these results, we propose that the local chromatin structure of the chicken α-globin enhancer plays a central role in its capacity to differentially regulate α-globin gene expression during erythroid differentiation and development.

scholarly journals Graph-based data integration predicts long-range regulatory interactions across the human genome

2014 ◽  
Author(s):  
Sofie Demeyer ◽  
Tom Michoel
Keyword(s):  
Gene Expression ◽  
Long Range ◽  
Regulation Of Gene Expression ◽  
Cell Types ◽  
Exon Array ◽  
Regulatory Elements ◽  
Computational Method ◽  
Open Chromatin ◽  
Transcription Start Sites ◽  
Distal Regulatory Elements

Transcriptional regulation of gene expression is one of the main processes that affect cell diversification from a single set of genes. Regulatory proteins often interact with DNA regions located distally from the transcription start sites (TSS) of the genes. We developed a computational method that combines open chromatin and gene expression information for a large number of cell types to identify these distal regulatory elements. Our method builds correlation graphs for publicly available DNase-seq and exon array datasets with matching samples and uses graph-based methods to filter findings supported by multiple datasets and remove indirect interactions. The resulting set of interactions was validated with both anecdotal information of known long-range interactions and unbiased experimental data deduced from Hi-C and CAGE experiments. Our results provide a novel set of high-confidence candidate open chromatin regions involved in gene regulation, often located several Mb away from the TSS of their target gene.

scholarly journals PESCA: A scalable platform for the development of cell-type-specific viral drivers

2019 ◽  
Author(s):  
Sinisa Hrvatin ◽  
Christopher P. Tzeng ◽  
M. Aurel Nagy ◽  
Hume Stroud ◽  
Charalampia Koutsioumpa ◽  
...  
Keyword(s):  
Gene Expression ◽  
Heterologous Gene Expression ◽  
Single Cells ◽  
Cell Types ◽  
Regulatory Elements ◽  
Functional Evaluation ◽  
Cell Type ◽  
Cell Type Specificity ◽  
Enhancer Activity ◽  
Cell Type Specific

AbstractEnhancers are the primary DNA regulatory elements that confer cell type specificity of gene expression. Recent studies characterizing individual enhancers have revealed their potential to direct heterologous gene expression in a highly cell-type-specific manner. However, it has not yet been possible to systematically identify and test the function of enhancers for each of the many cell types in an organism. We have developed PESCA, a scalable and generalizable method that leverages ATAC- and single-cell RNA-sequencing protocols, to characterize cell-type-specific enhancers that should enable genetic access and perturbation of gene function across mammalian cell types. Focusing on the highly heterogeneous mammalian cerebral cortex, we apply PESCA to find enhancers and generate viral reagents capable of accessing and manipulating a subset of somatostatin-expressing cortical interneurons with high specificity. This study demonstrates the utility of this platform for developing new cell-type-specific viral reagents, with significant implications for both basic and translational research.One sentence summaryHighly paralleled functional evaluation of enhancer activity in single cells generates new cell-type-specific tools with broad medical and scientific applications.

scholarly journals Integrated transcriptomics and epigenomics reveal chamber-specific and species-specific characteristics of human and mouse hearts

PLoS Biology ◽  
2021 ◽  
Vol 19 (5) ◽  
pp. e3001229
Author(s):  
Junpeng Gao ◽  
Yuxuan Zheng ◽  
Lin Li ◽  
Minjie Lu ◽  
Xiangjian Chen ◽  
...  
Keyword(s):  
Gene Expression ◽  
Dna Methylation ◽  
Human Heart ◽  
Nucleosome Occupancy ◽  
Expression Profiles ◽  
Regulation Of Gene Expression ◽  
Gene Expression Profiles ◽  
Chromatin Accessibility ◽  
Gene Body Methylation ◽  
Mammalian Heart

DNA methylation, chromatin accessibility, and gene expression represent different levels information in biological process, but a comprehensive multiomics analysis of the mammalian heart is lacking. Here, we applied nucleosome occupancy and methylome sequencing, which detected DNA methylation and chromatin accessibility simultaneously, as well as RNA-seq, for multiomics analysis of the 4 chambers of adult and fetal human hearts, and adult mouse hearts. Our results showed conserved region-specific patterns in the mammalian heart at transcriptome and DNA methylation level. Adult and fetal human hearts showed distinct features in DNA methylome, chromatin accessibility, and transcriptome. Novel long noncoding RNAs were identified in the human heart, and the gene expression profiles of major cardiovascular diseases associated genes were displayed. Furthermore, cross-species comparisons revealed human-specific and mouse-specific differentially expressed genes between the atria and ventricles. We also reported the relationship among multiomics and found there was a bell-shaped relationship between gene-body methylation and expression in the human heart. In general, our study provided comprehensive spatiotemporal and evolutionary insights into the regulation of gene expression in the heart.

scholarly journals Natural genetic variation affecting transcription factor spacing at regulatory regions is generally well tolerated

2020 ◽  
Author(s):  
Zeyang Shen ◽  
Jenhan Tao ◽  
Gregory J. Fonseca ◽  
Christopher K. Glass
Keyword(s):  
Gene Expression ◽  
Genetic Variation ◽  
Binding Sites ◽  
Regulation Of Gene Expression ◽  
Regulatory Elements ◽  
Nucleotide Polymorphisms ◽  
Enhancer Activity ◽  
Single Nucleotide ◽  
Natural Genetic Variation ◽  
Influence Gene Expression

AbstractRegulation of gene expression requires the combinatorial binding of sequence-specific transcription factors (TFs) at promoters and enhancers. Single nucleotide polymorphisms (SNPs) and short insertions and deletions (InDels) can influence gene expression by altering the sequences of TF binding sites. Prior studies also showed that alterations in the spacing between TF binding sites can influence promoter and enhancer activity. However, the relative importance of altered TF spacing has not been systematically analyzed in the context of natural genetic variation. Here, we exploit millions of InDels provided by five diverse strains of mice to globally investigate the effects of altered spacing on TF binding and local histone acetylation in macrophages. We find that spacing alterations resulting from InDels are generally well tolerated in comparison to genetic variants that directly alter TF binding sites. These findings have implications for interpretation of non-coding genetic variation and comparative analysis of regulatory elements across species.

scholarly journals Substantial DNA methylation differences between two major neuronal subtypes in human brain

2015 ◽  
Vol 44 (6) ◽  
pp. 2593-2612 ◽  
Author(s):  
Alexey Kozlenkov ◽  
Minghui Wang ◽  
Panos Roussos ◽  
Sergei Rudchenko ◽  
Mihaela Barbu ◽  
...  
Keyword(s):  
Gene Expression ◽  
Dna Methylation ◽  
Cell Types ◽  
Cpg Methylation ◽  
Projection Neurons ◽  
Specific Gene ◽  
Cpg Sites ◽  
Gaba Neurons ◽  
The Brain

Abstract The brain is built from a large number of cell types which have been historically classified using location, morphology and molecular markers. Recent research suggests an important role of epigenetics in shaping and maintaining cell identity in the brain. To elucidate the role of DNA methylation in neuronal differentiation, we developed a new protocol for separation of nuclei from the two major populations of human prefrontal cortex neurons—GABAergic interneurons and glutamatergic (GLU) projection neurons. Major differences between the neuronal subtypes were revealed in CpG, non-CpG and hydroxymethylation (hCpG). A dramatically greater number of undermethylated CpG sites in GLU versus GABA neurons were identified. These differences did not directly translate into differences in gene expression and did not stem from the differences in hCpG methylation, as more hCpG methylation was detected in GLU versus GABA neurons. Notably, a comparable number of undermethylated non-CpG sites were identified in GLU and GABA neurons, and non-CpG methylation was a better predictor of subtype-specific gene expression compared to CpG methylation. Regions that are differentially methylated in GABA and GLU neurons were significantly enriched for schizophrenia risk loci. Collectively, our findings suggest that functional differences between neuronal subtypes are linked to their epigenetic specification.

scholarly journals Functional impacts of non-coding RNA processing on enhancer activity and target gene expression

2019 ◽  
Vol 11 (10) ◽  
pp. 868-879 ◽  
Author(s):  
Evgenia Ntini ◽  
Annalisa Marsico
Keyword(s):  
Gene Expression ◽  
Rna Processing ◽  
Regulation Of Gene Expression ◽  
Regulatory Elements ◽  
Transcription Unit ◽  
Supporting Evidence ◽  
Enhancer Activity ◽  
Rna Transcripts ◽  
Non Coding Rna ◽  
Long Non Coding Rna

Abstract Tight regulation of gene expression is orchestrated by enhancers. Through recent research advancements, it is becoming clear that enhancers are not solely distal regulatory elements harboring transcription factor binding sites and decorated with specific histone marks, but they rather display signatures of active transcription, showing distinct degrees of transcription unit organization. Thereby, a substantial fraction of enhancers give rise to different species of non-coding RNA transcripts with an unprecedented range of potential functions. In this review, we bring together data from recent studies indicating that non-coding RNA transcription from active enhancers, as well as enhancer-produced long non-coding RNA transcripts, may modulate or define the functional regulatory potential of the cognate enhancer. In addition, we summarize supporting evidence that RNA processing of the enhancer-associated long non-coding RNA transcripts may constitute an additional layer of regulation of enhancer activity, which contributes to the control and final outcome of enhancer-targeted gene expression.

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