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CD4+ T cells From Children With Active Juvenile Idiopathic Arthritis Show Altered Chromatin Features Associated With Transcriptional Abnormalities (RNA-seq)

ABSTRACT: We used a multi-omics approach in an attempt to identify mechanisms driving the transcriptional abnormalities in peripheral blood CD4+ T cells of children with active JIA. We demonstrate that active JIA is associated with distinct alterations in CD4+ T cell chromatin, as assessed by ATAC-seq studies. However, 3D chromatin architecture, assessed by HiChIP and simultaneous mapping of CTCF anchors of chromatin loops, reveals that normal 3D chromatin architecture is largely preserved in JIA CD4+ T cells. However, overlapping CTCF binding, ATACseq, and RNAseq data with known JIA genetic risk loci demonstrated the presence of genetic influences on the observed transcriptional abnormalities and identified candidate target genes. These studies demonstrate the utility of multi-omics approaches for unraveling some of the most vexing questions regarding the pathobiology of autoimmune diseases.

ORGANISM(S): Homo sapiens

PROVIDER: GSE164213 | GEO | 2021/01/05

REPOSITORIES: GEO

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CD4+ T cells From Children With Active Juvenile Idiopathic Arthritis Show Altered Chromatin Features Associated With Transcriptional Abnormalities (ATAC-seq)

Project description:We used a multi-omics approach in an attempt to identify mechanisms driving the transcriptional abnormalities in peripheral blood CD4+ T cells of children with active JIA. We demonstrate that active JIA is associated with distinct alterations in CD4+ T cell chromatin, as assessed by ATAC-seq studies. However, 3D chromatin architecture, assessed by HiChIP and simultaneous mapping of CTCF anchors of chromatin loops, reveals that normal 3D chromatin architecture is largely preserved in JIA CD4+ T cells. However, overlapping CTCF binding, ATACseq, and RNAseq data with known JIA genetic risk loci demonstrated the presence of genetic influences on the observed transcriptional abnormalities and identified candidate target genes. These studies demonstrate the utility of multi-omics approaches for unraveling some of the most vexing questions regarding the pathobiology of autoimmune diseases.

2021-01-05 | GSE164214 | GEO

CD4+ T cells From Children With Active Juvenile Idiopathic Arthritis Show Altered Chromatin Features Associated With Transcriptional Abnormalities (ChIP-seq)

2021-01-05 | GSE164212 | GEO

Acute depletion of CTCF rewires genome-wide chromatin accessibility

Project description:The transcription factor CTCF appears indispensable in defining topologically associated domain boundaries and maintaining chromatin loop structures within these domains, supported by numerous functional studies. However, acute depletion of CTCF globally reduces chromatin interactions but does not significantly alter transcription. Here we systematically integrated multi-omics data including ATAC-seq, RNA-seq, WGBS, Hi-C, Cut&Run, CRISPR-Cas9 survival dropout screening, time-solved deep proteomic and phosphoproteomic analyses in cells carrying auxin-induced degron at endogenous CTCF locus. Acute CTCF protein degradation markedly rewired genome-wide chromatin accessibility. Increased accessible chromatin regions were largely located adjacent to CTCF-binding sites at promoter regions and insulator sites and were associated with enhanced transcription of nearby genes. In addition, we used CTCF-associated multi-omics data to establish a combinatorial data analysis pipeline to discover CTCF co-regulatory partners in regulating downstream gene expression. We successfully identified 40 candidates, including multiple established partners (i.e., MYC) supported by all layers of evidence. Interestingly, many CTCF co-regulators (e.g., YY1, ZBTB7A) that have evident alterations of respective downstream gene expression do not show changes at their expression levels across the multi-omics measurements upon acute CTCF loss, highlighting the strength of our system to discover hidden co-regulatory partners associated with CTCF-mediated transcription. This study highlights CTCF loss rewires genome-wide chromatin accessibility, which plays a critical role in transcriptional regulation

2021-07-04 | PXD026484 | Pride

Project description:3d-coral-multi-omics

| PRJNA692629 | ENA

p63 cooperates with CTCF to modulate chromatin accessibility and architecture in skin keratinocytes

Project description:Here we integrated multi-omics profiles including transcriptomics, DNA accessibility and capture Hi-C data to explore how p63 shapes local chromatin architecture in skin keratinocytes isolated from EEC syndrome patients. Surprisingly, we observed decreased chromatin accessibility in a number of DNA looping nodes which were co-mediated by p63 and CTCF. Our findings not only identified a new aspect of the bookmark function of p63, but also shed light on the disease mechanism underlined p63 dysfunction. Therefore, we propose p63 as a spatial genome organizer by modulating a subset of DNA loops with CTCF and therefore fine-tuning transcription programs required for skin keratinocytes.

2019-06-21 | GSE123711 | GEO

Homo sapiens

Project description:CTCF-Mediated Human 3D Genome Architecture Reveals Chromatin Topology for Transcription

| PRJNA295132 | ENA

Simultaneous profiling of chromatin architecture and transcription in single cells

Project description:Three-dimensional (3D) chromatin structure plays a crucial role in development and diseases, which are associated with transcriptional changes. However, given the heterogeneity in single-cell chromatin architecture and transcription, the regulatory relationship between 3D chromatin structure and gene expression is difficult to explain based on the cell populations. Here we developed a single-cell multimodal omics method for simultaneously detecting chromatin architecture and mRNA expression by sequencing (scCARE-seq). Applying scCARE-seq to examine chromatin architecture and transcription from naïve to primed single mouse embryonic stem cells (mESCs), we observed correlated changes between 3D chromatin structure and expression in the cell fate transition. In addition, we defined cell cycle phase of each cell through chromatin architecture extracted by CARE-seq, and found that periodic changes in chromatin architecture were in parallel with transcription during the cell cycle. These findings indicate that scCARE-seq allows comprehensive analysis of chromatin architecture and transcription in the same single cell.

2023-07-08 | GSE211395 | GEO

Chd4 regulates intra-chromatin looping by concealing CTCF sites from B2 SINEs in mESCs

Project description:CTCF plays a critical role in maintaining the three-dimensional (3D) chromatin organization, which is important for gene regulation, as it allows distal regulatory elements to come into proximity with one another. However, the detailed mechanism responsible for establishing and maintaining the recruitment of CTCF remains elusive. Here, we use in situ Hi-C to show that the ATP-dependent chromatin remodeler, Chd4, regulates intra-chromatin looping by controlling chromatin accessibility to conceal aberrant CTCF-binding sites in mouse embryonic stem cells (mESCs). These aberrant CTCF-binding sites are embedded in B2 SINEs and are localized within the interior of chromatin loops. In the absence of Chd4, the aberrant CTCF-binding sites become accessible and improper CTCF recruitment occurs, resulting in disorganization of the 3D chromatin architecture and subsequent disruption of enhancer-promoter interactions and the transcription of the corresponding genes. These results indicate that Chd4 regulates adequate transcription of mESCs by securing the proper 3D chromatin organization.

2022-05-10 | GSE172392 | GEO

Epigenetic profiling of Juvenile Idiopathic Arthritits (JIA) patients

Project description:With H3K27ac chromatin immunoprecipitation we identified a disease-specific, inflammation-associated, (super-)enhancer signature in JIA patient synovial fluid-derived CD4+ memory/effector T cells. This signature consists of unique pathogenesis-associated epigenetic changes which extend beyond general T cell activation-induced alterations, indicating that disease-specific (super-)enhancers contribute to JIA pathogenesis. In addition, our analysis shows that there is a profound enrichment of JIA-related SNPs in (super-)enhancers in JIA patients compared to controls, illustrating the importance of these non-coding regions for disease pathogenesis. H3K27ac ChIP-sequencing of CD4+ memory/effector T cells derived from peripheral blood (PB) from healthy controls (HC) and PB or synovial fluid (SF) from JIA patients.

2015-09-15 | E-GEOD-71596 | biostudies-arrayexpress

Acute depletion of CTCF rewires genome-wide chromatin accessibility

Project description:Accumulated data suggest that transcription factor CTCF is indispensable to define topologically associated domain (TAD) boundaries and to maintain intra-TAD chromatin loop structures. However, upon genome-wide acute depletion of CTCF, the discrepancy between global reduction of chromatin interactions and minimal alteration of transcription has been evidently observed. To understand CTCF’s direct role in chromatin accessibility and global transcriptional regulation, we have systematically integrated data collected from ATAC-seq, RNA-seq, whole genome bisulfite-seq, Cut&Run and HiC in a previously established CTCF-miniAID knock-in cell lines. Acute degradation of CTCF markedly rewires genome-wide chromatin accessibility but not DNA methylation. Differentially altered ATAC-seq peaks are highly associated with adjacent CTCF binding sites, supporting the direct link between CTCF occupancy and its surrounding chromatin accessibility. Increased ATAC-seq peaks upon CTCF loss are notably associated with enhanced transcription at promoter regions and insulator sites, while decreased ATAC-seq peaks are significantly enriched at DNA loops. Furthermore, using CTCF associated multi-Omics data we have established a combinatorial data analysis pipeline to discover novel CTCF mediated insulators in the genome, by which we have successfully identified 67 novel insulators at non-coding regions distal to promoters. Functional CRISPR interference (CRISPRi) unconstrained the repressive transcriptional regulation of target genes. In sum, using CTCF acute depletion cell model and multi-Omics analysis, we concluded that CTCF loss rewires genome-wide chromatin accessibility, which plays a critical role for transcriptional regulation.

2021-08-26 | GSE153237 | GEO

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