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TE-associated chromatin variation in mice livers

ABSTRACT: Chromatin accessibility is a hallmark of active regulatory function in the genome and variation of chromatin accessibility across individuals has been shown to contribute to complex traits and disease susceptibility. However, the mechanisms responsible for chromatin variation among different individuals and how this variation contributes to phenotypic diversity remain poorly understood. We examined chromatin accessibility variation in liver tissue from seven strains of adult mice that have phenotypic diversity in response to a high-fat/high-sucrose diet. Remarkably, nearly 40% of the loci with the greatest degree of chromatin variability across the strains are associated with transposable elements (TEs), with evolutionarily younger TEs being particularly enriched for regions of chromatin variation. We found that evolutionary younger and older TEs have differential chromatin accessibility profiles and are enriched for binding sites of different transcription factors, indicating the role of TEs in the evolution of regulatory networks in the liver. We also demonstrate that TE polymorphisms and epigenetic regulation of TEs contribute to regulatory variation across different strains through providing binding sites for liver transcription factors. Intriguingly, variable chromatin loci that are associated with liver metabolism are primarily TE-associated. We demonstrate that TEs contribute to regulatory variation in liver and have downstream effects on metabolism. Our data reveal TEs as a novel and important contributor to regulatory and phenotypic variation in the liver and suggest that regulatory variation at TEs is a major contributor to phenotypic variation in populations.

ORGANISM(S): Mus musculus

PROVIDER: GSE75770 | GEO | 2016/07/14

SECONDARY ACCESSION(S): PRJNA305303

REPOSITORIES: GEO

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TE-associated chromatin variation in mice livers

Project description:Chromatin accessibility is a hallmark of active regulatory function in the genome and variation of chromatin accessibility across individuals has been shown to contribute to complex traits and disease susceptibility. However, the mechanisms responsible for chromatin variation among different individuals and how this variation contributes to phenotypic diversity remain poorly understood. We examined chromatin accessibility variation in liver tissue from seven strains of adult mice that have phenotypic diversity in response to a high-fat/high-sucrose diet. Remarkably, nearly 40% of the loci with the greatest degree of chromatin variability across the strains are associated with transposable elements (TEs), with evolutionarily younger TEs being particularly enriched for regions of chromatin variation. We found that evolutionary younger and older TEs have differential chromatin accessibility profiles and are enriched for binding sites of different transcription factors, indicating the role of TEs in the evolution of regulatory networks in the liver. We also demonstrate that TE polymorphisms and epigenetic regulation of TEs contribute to regulatory variation across different strains through providing binding sites for liver transcription factors. Intriguingly, variable chromatin loci that are associated with liver metabolism are primarily TE-associated. We demonstrate that TEs contribute to regulatory variation in liver and have downstream effects on metabolism. Our data reveal TEs as a novel and important contributor to regulatory and phenotypic variation in the liver and suggest that regulatory variation at TEs is a major contributor to phenotypic variation in populations. Examination of chromatin accessibility with FAIRE-seq in livers of male mice (A/J, AKR/J, BALB/cJ, C57BL/6J, C3H/HeJ, CBA/J, DBA/2J, BXH2/TyJ, and BXH19/TyJ) fed a high-fat, high-sucrose diet.

2016-07-14 | E-GEOD-75770 | biostudies-arrayexpress

Regulatory DNA in A. thaliana can tolerate high levels of sequence divergence

Project description:Variation in regulatory DNA is thought to drive evolution. Cross-species comparisons of regulatory DNA have provided evidence for both weak purifying selection and substantial turnover in regulatory regions. However, disruption of transcription factor binding sites can affect the expression of neighboring genes. Thus, the base-pair level functional annotation of regulatory DNA has proven challenging. Here, we explore regulatory DNA variation and its functional consequences in genetically diverse strains of the plant Arabidopsis thaliana, which largely maintain the positional homology of regulatory DNA. Using chromatin accessibility to delineate regulatory DNA genome-wide, we find that 15% of approximately 50,000 regulatory sites varied in accessibility among strains. Some of these accessibility differences are associated with extensive underlying sequence variation, encompassing many deletions and dramatically hypervariable sequence. For the majority of such regulatory sites, nearby gene expression was similar, despite this large genetic variation. However, among all regulatory sites, those with both high levels of sequence variation and differential chromatin accessibility are the most likely to reside near genes with differential expression among strains. Unexpectedly, the vast majority of regulatory sites that differed in chromatin accessibility among strains show little variation in the underlying DNA sequence, implicating variation in upstream regulators.

2017-08-15 | GSE101952 | GEO

Single-cell chromatin accessibility data using scATAC-seq

Project description:Cell-to-cell variation is a universal feature of life that impacts a wide range of biological phenomena, from developmental plasticity to tumor heterogeneity. While recent advances have improved our ability to document cellular phenotypic variation the fundamental mechanisms that generate variability from identical DNA sequences remain elusive. Here we reveal the landscape and principles of cellular DNA regulatory variation by developing a robust method for mapping the accessible genome of individual cells via assay of transposase accessible chromatin sequencing (ATAC-seq). Single-cell ATAC-seq (scATAC-seq) maps from hundreds of single-cells in aggregate closely resemble accessibility profiles from tens of millions of cells and provides insights into cell-to-cell variation. Accessibility variance is systematically associated with specific trans-factors and cis-elements, and we discover combinations of trans-factors associated with either induction or suppression of cell-to-cell variability. We further identify sets of trans-factors associated with cell-type specific accessibility variance across 6 cell types. Targeted perturbations of cell cycle or transcription factor signaling evoke stimulus-specific changes in this observed variability. The pattern of accessibility variation in cis across the genome recapitulates chromosome topological domains de novo, linking single-cell accessibility variation to three-dimensional genome organization. All together, single-cell analysis of DNA accessibility provides new insight into cellular variation of the “regulome.” Profiles of single cell epigenomes, assayed using scATAC-seq, across 8 cell types and 4 targeted cell manipulations. The complete data set contains a total of 1,632 assayed wells.

2015-06-17 | E-GEOD-65360 | biostudies-arrayexpress

Variation in chromatin accessibility is a key determinant of heritable variation in gene expression

Project description:While it is well established that variation in gene expression levels can be influenced by single nucleotide polymorphisms (SNPs), little is known about the regulatory mechanisms by which this occurs. To address this gap, we used DNaseI sequencing to measure genome-wide chromatin accessibility in 70 Yoruba lymphoblastoid cell lines (LCLs), for which genome-wide genotypes and estimates of gene expression levels based on RNA-sequencing are also available. We obtained a total of 2.8 billion uniquely mapped DNase-seq reads, which allowed us to produce genome-wide maps of chromatin accessibility for each individual. We identified 7,759 locations at which DNase-seq read depth correlates significantly with variation at a nearby SNP or indel (FDR=10%). We call such variants 'chromatin accessibility Quantitative Trait Loci' (or caQTLs). Most caQTLs lie within or very near the target DNaseI hypersensitive sites, and they are strongly enriched within inferred transcription factor binding sites. We find that a substantial fraction (14%) of caQTLs are also significantly associated with variation in the expression levels of nearby genes (namely, these loci are also classified as eQTLs), suggesting that changes in chromatin accessibility or transcription factor binding frequently lead to gene expression changes. Conversely, 12% of eQTL SNPs are also classified as caQTLs and, accounting for incomplete power, we estimate that the true fraction may be as high as 41%. Our observations indicate that caQTLs are abundant in the human genome, and are likely to be significant contributors to phenotypic variation. DNaseI-Seq on 70 YRI Hapmap cell lines. Each individual sequenced on several lanes of a flow cell on the Illumina Genome Analyzer II

2012-01-26 | E-GEOD-31388 | biostudies-arrayexpress

Evolution of diapause in the African killifish by remodeling ancient gene regulatory landscape

Project description:Suspended animation (e.g. hibernation, diapause) allows organisms to survive extreme environments. But the mechanisms underlying the evolution of suspended animation states are unknown. The African turquoise killifish has evolved diapause as a form of suspended development to survive the complete drought that occurs every summer. Here, we show that gene duplicates – paralogs – exhibit specialized expression in diapause compared to normal development in the African turquoise killifish. Surprisingly, paralogs with specialized expression in diapause are evolutionarily very ancient and are present even in vertebrates that do not exhibit diapause. To determine if evolution of diapause is due to the regulatory landscape rewiring at ancient paralogs, we assessed chromatin accessibility genome-wide in fish species with or without diapause. This analysis revealed an evolutionary recent increase in chromatin accessibility at very ancient paralogs in African turquoise killifish. The increase in chromatin accessibility is linked to the presence of new binding sites for transcription factors, likely due to de novo mutations and transposable element (TE) insertion. Interestingly, accessible chromatin regions in diapause are enriched for lipid metabolism genes, and our lipidomics studies uncover a striking difference in lipid species in African turquoise killifish diapause, which could be critical for long-term survival. Together, our results show that diapause likely originated by repurposing pre-existing gene programs via recent changes in the regulatory landscape. This work raises the possibility that suspended animation programs could be reactivated in other species for long-term preservation via transcription factor remodeling and suggests a mechanism for how complex adaptations evolve in nature.

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Genetic effects on liver chromatin accessibility identify disease regulatory variants

Project description:Genetic effects on liver chromatin accessibility identify disease regulatory variants

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Natural variation in processability of individual Arabidopsis thaliana microRNAs

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2012-10-31 | E-GEOD-32927 | biostudies-arrayexpress

Expression data from TSA-treated Plasmodium

Project description:Variation of surface adhesins is a critical mediator of virulence and immune evasion in many medically important microbes. Phenotypic switching has been linked to transcriptional changes and the function of chromatin proteins, but the determinants of the rate of phenotypic switching remain poorly defined. We analyzed epigenetic switching of the Plasmodium falciparum erythrocyte invasion ligand PfRh4. By introducing a prokaryotic Dam methylase, we demonstrate that parasites selected for in vivo PfRh4 activation show a reversible increase in promoter accessibility while exhibiting perinuclear repositioning of the locus from a silent to a conserved activation domain. Forced activation of a proximal gene results in a similar level of repositioning of the PfRh4 locus into this domain and a concomitant increase in PfRh4 activation in a sub-population of parasites, with promoter accessibility occurring only at actively transcribed loci. Thus, we reveal two distinct epigenetic mechanisms regulating the expression of a malaria virulence gene. To examine the correlation between changes in gene expression induced by treatment with a high dose of trichostatin A (TSA) and the associated changes in chromatin accessibility. Plasmodium falciparum was treated (or not, control) with 100nm or 500nm TSA, and then the expression profiles were analyzed.

2012-10-13 | E-GEOD-41567 | biostudies-arrayexpress

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