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 Transposable elements contribute to the genomic response to insecticides in Drosophila melanogaster

2020 ◽  
Vol 375 (1795) ◽  
pp. 20190341 ◽  
Author(s):  
Judit Salces-Ortiz ◽  
Carlos Vargas-Chavez ◽  
Lain Guio ◽  
Gabriel E. Rech ◽  
Josefa González
Keyword(s):  
Gene Expression ◽  
Drosophila Melanogaster ◽  
Regulatory Networks ◽  
Regulation Of Gene Expression ◽  
Nucleotide Polymorphisms ◽  
Rna Seq ◽  
Organophosphate Insecticide ◽  
Single Nucleotide ◽  
Insecticide Exposure ◽  
Genomic Response

Most of the genotype–phenotype analyses to date have largely centred attention on single nucleotide polymorphisms. However, transposable element (TE) insertions have arisen as a plausible addition to the study of the genotypic–phenotypic link because of to their role in genome function and evolution. In this work, we investigate the contribution of TE insertions to the regulation of gene expression in response to insecticides. We exposed four Drosophila melanogaster strains to malathion, a commonly used organophosphate insecticide. By combining information from different approaches, including RNA-seq and ATAC-seq, we found that TEs can contribute to the regulation of gene expression under insecticide exposure by rewiring cis -regulatory networks. This article is part of a discussion meeting issue ‘Crossroads between transposons and gene regulation’.

scholarly journals Quadruplex-single nucleotide polymorphisms (Quad-SNP) influence gene expression difference among individuals

2012 ◽  
Vol 40 (9) ◽  
pp. 3800-3811 ◽  
Author(s):  
Aradhita Baral ◽  
Pankaj Kumar ◽  
Rashi Halder ◽  
Prithvi Mani ◽  
Vinod Kumar Yadav ◽  
...  
Keyword(s):  
Gene Expression ◽  
Single Nucleotide Polymorphisms ◽  
Gene Expression Difference ◽  
Nucleotide Polymorphisms ◽  
Single Nucleotide ◽  
Expression Difference ◽  
Influence Gene Expression

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 Genetic and Epigenetic Fine Mapping of Complex Trait Associated Loci in the Human Liver

2018 ◽  
Author(s):  
Minal Çalışkan ◽  
Elisabetta Manduchi ◽  
H. Shanker Rao ◽  
Julian A Segert ◽  
Marcia Holsbach Beltrame ◽  
...  
Keyword(s):  
Gene Expression ◽  
Genetic Variation ◽  
Histone Modification ◽  
Human Liver ◽  
Complex Disease ◽  
Regulation Of Gene Expression ◽  
Regulatory Elements ◽  
Chromatin Interaction ◽  
Genome Wide ◽  
The Impact

ABSTRACTDeciphering the impact of genetic variation on gene regulation is fundamental to understanding common, complex human diseases. Although histone modifications are important markers of gene regulatory regions of the genome, any specific histone modification has not been assayed in more than a few individuals in the human liver. As a result, the impacts of genetic variation that direct histone modification states in the liver are poorly understood. Here, we generate the most comprehensive genome-wide dataset of two epigenetic marks, H3K4me3 and H3K27ac, and annotate thousands of putative regulatory elements in the human liver. We integrate these findings with genome-wide gene expression data collected from the same human liver tissues and high-resolution promoter-focused chromatin interaction maps collected from human liver-derived HepG2 cells. We demonstrate widespread functional consequences of natural genetic variation on putative regulatory element activity and gene expression levels. Leveraging these extensive datasets, we fine-map a total of 77 GWAS loci that have been associated with at least one complex phenotype. Our results contribute to the repertoire of genes and regulatory mechanisms governing complex disease development and further the basic understanding of genetic and epigenetic regulation of gene expression in the human liver tissue.

scholarly journals Impact of Viral Activators and Epigenetic Regulators on HIV-1 LTRs Containing Naturally Occurring Single Nucleotide Polymorphisms

2015 ◽  
Vol 2015 ◽  
pp. 1-14 ◽  
Author(s):  
Sonia Shah ◽  
Vanessa Pirrone ◽  
Aikaterini Alexaki ◽  
Michael R. Nonnemacher ◽  
Brian Wigdahl
Keyword(s):  
Gene Expression ◽  
Single Nucleotide Polymorphisms ◽  
Cell Lines ◽  
Trichostatin A ◽  
Regulatory Elements ◽  
Nucleotide Polymorphisms ◽  
Monocytic Cell ◽  
Single Nucleotide ◽  
Cell Clones ◽  
Hiv 1

Following human immunodeficiency virus type 1 (HIV-1) integration into host cell DNA, the viral promoter can become transcriptionally silent in the absence of appropriate signals and factors. HIV-1 gene expression is dependent on regulatory elements contained within the long terminal repeat (LTR) that drive the synthesis of viral RNAs and proteins through interaction with multiple host and viral factors. Previous studies identified single nucleotide polymorphisms (SNPs) within CCAAT/enhancer binding protein (C/EBP) site I and Sp site III (3T, C-to-T change at position 3, and 5T, C-to-T change at position 5 of the binding site, respectively, when compared to the consensus B sequence) that are low affinity binding sites and correlate with more advanced stages of HIV-1 disease. Stably transfected cell lines containing the wild type, 3T, 5T, and 3T5T LTRs were developed utilizing bone marrow progenitor, T, and monocytic cell lines to explore the LTR phenotypes associated with these genotypic changes from an integrated chromatin-based microenvironment. Results suggest that in nonexpressing cell clones LTR-driven gene expression occurs in a SNP-specific manner in response to LTR activation or treatment with trichostatin A treatment, indicating a possible cell type and SNP-specific mechanism behind the epigenetic control of LTR activation.

scholarly journals Mechanisms underlying divergent responses of genetically distinct macrophages to IL-4

2021 ◽  
Vol 7 (25) ◽  
pp. eabf9808
Author(s):  
Marten A. Hoeksema ◽  
Zeyang Shen ◽  
Inge R. Holtman ◽  
An Zheng ◽  
Nathan J. Spann ◽  
...  
Keyword(s):  
Gene Expression ◽  
Genetic Variation ◽  
Disease Risk ◽  
Phenotypic Diversity ◽  
Inbred Strains ◽  
Dynamic Responses ◽  
Interleukin 4 ◽  
Nucleotide Polymorphisms ◽  
Enhancer Activity ◽  
Inbred Strains Of Mice

Mechanisms by which noncoding genetic variation influences gene expression remain only partially understood but are considered to be major determinants of phenotypic diversity and disease risk. Here, we evaluated effects of >50 million single-nucleotide polymorphisms and short insertions/deletions provided by five inbred strains of mice on the responses of macrophages to interleukin-4 (IL-4), a cytokine that plays pleiotropic roles in immunity and tissue homeostasis. Of >600 genes induced >2-fold by IL-4 across the five strains, only 26 genes reached this threshold in all strains. By applying deep learning and motif mutation analyses to epigenetic data for macrophages from each strain, we identified the dominant combinations of lineage-determining and signal-dependent transcription factors driving IL-4 enhancer activation. These studies further revealed mechanisms by which noncoding genetic variation influences absolute levels of enhancer activity and their dynamic responses to IL-4, thereby contributing to strain-differential patterns of gene expression and phenotypic diversity.

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.

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