Landscape of stimulation-responsive chromatin across diverse human immune cells

Calderon, Diego; Nguyen, Michelle; Mezger, Anja; Kathiria, Arwa S.; Müller, Fabian; Nguyen, Vinh; Lescano, Ninnia; Wu, Beijing; Trombetta, John J.; Ribado, Jessica V.; Knowles, David A.; Gao, Ziyue; Blaeschke, Franziska; Parent, Audrey V.; Burt, Trevor D.; Anderson, Mark S.; Criswell, Lindsey A.; Greenleaf, William J.; Marson, Alexander; Pritchard, Jonathan K.

doi:10.1038/s41588-019-0505-9

Cited by 229 publications

(388 citation statements)

References 68 publications

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“…We did not find either to contribute substantially to the gene expression response we observed. There are minimal changes in accessibility following hypoxia, which is in contrast to observations of studies that considered stimulation of immune cell types (Alasoo et al, 2018;Calderon et al, 2019;Pacis et al, 2015). This could reflect cell type specificity in response to stress, or the specificity of the cellular response to different stressors.…”

Section: Mechanisms Behind Response Genes and Dynamic Eqtlscontrasting

confidence: 58%

Dynamic effects of genetic variation on gene expression revealed following hypoxic stress in cardiomyocytes

Ward

Banovich²,

Sarkar³

et al. 2020

Preprint

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One life-threatening outcome of cardiovascular disease is myocardial infarction, where cardiomyocytes are deprived of oxygen. To study inter-individual differences in response to hypoxia, we established an in vitro model of induced pluripotent stem cell-derived cardiomyocytes from 15 individuals. We measured gene expression levels, chromatin accessibility, and methylation levels in four culturing conditions that correspond to normoxia, hypoxia and short or long-term reoxygenation. We characterized thousands of gene regulatory changes as the cells transition between conditions. Using available genotypes, we identified 1,573 genes with a cis expression quantitative locus (eQTL) in at least one condition, as well as 367 dynamic eQTLs, which are classified as eQTLs in at least one, but not in all conditions. A subset of genes with dynamic eQTLs is associated with complex traits and disease. Our data demonstrate how dynamic genetic effects on gene expression, which are likely relevant for disease, can be uncovered under stress.

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Section: Mechanisms Behind Response Genes and Dynamic Eqtlscontrasting

confidence: 58%

Dynamic effects of genetic variation on gene expression revealed following hypoxic stress in cardiomyocytes

Ward

Banovich²,

Sarkar³

et al. 2020

Preprint

View full text Add to dashboard Cite

show abstract

“…Previous studies on the induction of T cell tolerance have mainly focused on single genes or transcription factors (TFs), such as Egr-2, nuclear factor of activated T cells (NFAT), and Jun (Lynn et al, 2019; Safford et al, 2005; Soto-Nieves et al, 2009). Recent advances in genome sequencing technologies, including Hi-C (Genome-wide chromosome conformation capture), assays for transposase-accessible chromatin with high-throughput sequencing (ATAC-seq) and RNA-seq, have enabled gene expression and epigenetic measurements and have revealed variability in immune-cell development and aging (Calderon et al, 2019; Miraldi et al, 2019; Philip et al, 2017). For example, by RNA-seq and ATAC-seq, Mognol et al defined a pattern of chromatin accessibility specific for T-cell exhaustion (Mognol et al, 2017), which was characterized by enrichment for consensus binding motifs for the NR4A and NFAT TFs.…”

Section: Introductionmentioning

confidence: 99%

Three-dimensional genome structure and chromatin accessibility reorganization duringin vivoinduction of human T cell tolerance

Guo

Hou

et al. 2020

Preprint

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Achieving T cell tolerance is a pivotal goal for the field of transplantation and autoimmune diseases. Here, we characterized the gene expression profiles, 3D genome architecture and chromatin accessibility in human steady-state and tolerant T cells, which had been induced in healthy donors by granulocyte-colony-stimulating factor in vivo. We provided the first high-resolution 3D genomic landscape of human tolerant T cells in vivo and identified highly expressed suppressor of cytokine signaling 1 (SOCS1), which is essential for maintaining T cell tolerance and was validated by ex vivo experiments. Mechanistically, SOCS1 is activated by STAT3, which mediates a new interaction between the SOCS1 locus and downstream super-enhancers and is accompanied by the disruption of the CTCF loop between the SOCS1 locus and upstream heterochromatin. This competitive regulation pattern between STAT3 and CTCF is present in the whole genome.Our study defines a regulatory model of transcription factors and provides insight into the induction of immune tolerance.3

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“…The impact of signalling pathway activation on chromatin accessibility is less well established. Calderon et al used distinct stimuli to induce biologically relevant responses in a range of T and B cell subsets and monocytes and NK cells and assessed chromatin accessibility via ATAC-seq [30]. Overall they found dramatic changes in the chromatin landscapes of the B and T cells, but limited effects in innate lineage cells.…”

Section: Discussionmentioning

confidence: 99%

Dynamic chromatin accessibility landscape changes following interleukin-1 stimulation

Barter

Cheung

Falk

et al. 2020

Preprint

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Genome-wide methods for examining chromatin modification provide detailed information on regulatory regions of the genome. Dynamic modifications of chromatin allow rapid access of the gene regulatory machinery to condensed genomic regions facilitating subsequent gene expression. Inflammatory cytokine stimulation of cells can cause rapid gene expression changes through direct signalling pathway-mediated transcription factor activation and regulatory element binding.Here we used the Assay for Transposase Accessible Chromatin with high-throughput sequencing (ATAC-seq) to assess regions of the genome that are differentially accessible following treatment of cells with interleukin-1 (IL-1). We identified 126,483 open chromatin regions, with 241 regions significantly differentially accessible following stimulation, with 64 and 177 more or less accessible, respectively. These differentially accessible regions predominantly correspond to regions of the genome marked as enhancers. Motif searching identified an overrepresentation of a number of transcription factors, most notably RelA in the regions becoming more accessible, with analysis of ChIP-seq data confirmed RelA binding to these regions. A significant correlation in differential chromatin accessibility and gene expression was also observed.Functionality in regulating gene expression was confirmed using CRISPR/Cas9 genome-editing to delete regions for that became more accessible following stimulation in the genes MMP13, IKBKE and C1QTNF1. These same regions were also accessible for activation using a dCas9-transcriptional activator and showed enhancer activity in a cellular model.Together, these data describe and functionally validate a number of dynamically accessible chromatin regions involved in inflammatory signalling.

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Landscape of stimulation-responsive chromatin across diverse human immune cells

Cited by 229 publications

References 68 publications

Dynamic effects of genetic variation on gene expression revealed following hypoxic stress in cardiomyocytes

Dynamic effects of genetic variation on gene expression revealed following hypoxic stress in cardiomyocytes

Three-dimensional genome structure and chromatin accessibility reorganization duringin vivoinduction of human T cell tolerance

Dynamic chromatin accessibility landscape changes following interleukin-1 stimulation

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