Homo sapiens
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA295132 | ENA |
REPOSITORIES: ENA
Similar Datasets
Project description:Spatial genome organization and its effect on transcription remains a fundamental biological question. We applied an advanced ChIA-PET strategy to comprehensively map higher-order chromosome folding and chromatin interactions mediated by CTCF and RNAPII with haplotype specificity and nucleotide resolution in different human cell lineages. We find that CTCF-mediated interaction anchors serve as structural foci for spatial organization of constitutive genes concordant with CTCF-motif orientation, whereas RNAPII interacts within these structures by selectively drawing cell-type-specific genes towards CTCF-foci and forming RNAPII foci for coordinated transcription. Furthermore, allelic-variants linked to disease susceptibility are found to impact chromatin topology and transcriptional regulation. Importantly, 3D-genome simulation suggested a model of chromatin folding around chromosomal axes, where CTCF involves in defining the interface between condensed and open compartments for structural regulation. Our new 3D-genome strategy thus provides novel insights to explore the topological mechanism of human variations and diseases.
2015-12-11 | GSE72816 | GEO
Project description:<p>Metabolic lesions with pleiotropic effects on epigenetic regulation and other cellular processes are widely implicated in cancer, yet their oncogenic mechanisms remain poorly understood. Succinate dehydrogenase (SDH) deficiency causes a subset of gastrointestinal stromal tumors (GISTs) with DNA hyper-methylation. Here we associate this hyper-methylation with changes in chromosome topology that activate oncogenic programs. To investigate epigenetic alterations in this disease, we systematically mapped DNA methylation, CTCF insulators, enhancers and chromosome topology in KIT-mutant, PDGFRA-mutant and SDH-deficient GISTs. Although these respective subtypes share similar enhancer landscapes, we identified hundreds of putative insulators where DNA methylation replaced CTCF binding in SDH-deficient GISTs. We focused on disrupted insulators that partitions super-enhancers from FGF3, FGF4 and the KIT oncogene. Recurrent loss of this insulator alters locus topology in SDH-deficient GISTs, allowing aberrant physical interaction between enhancers and oncogenes. CRISPR-mediated excision of the corresponding CTCF motif in an SDH-intact model disrupted the boundary and up-regulated FGFs and KIT expression. Our findings reveal how a metabolic lesion destabilizes chromatin structure to facilitate the initiation and selection of epigenetic alterations that drive oncogenic programs in the absence of canonical mutations.</p>
| phs001906 | dbGaP
Project description:Spatial genome organization is critical for precise gene regulation during development. Special AT-rich sequence binding protein 1 (SATB1) has long been proposed to act as a global chromatin loop organizer in T cells. However, the exact functions of SATB1 in genome organization remain elusive. Here we show that the depletion of SATB1 in human and murine T cells led to transcriptional dysregulation for genes involved in T cell activation, as well as alterations of 3D genome architecture at multiple scales, including the A/B compartment, topologically associating domains (TADs), and loops. Importantly, SATB1 extensively colocalizes with CTCF throughout the genome. Depletion of SATB1 led to increased chromatin contacts among and across the SATB1/CTCF co-occupied sites, thereby affecting the transcription of critical genes involved in T cell activation. The loss of SATB1 did not affect the genome-wide occupancy of CTCF, but significantly reduced the retention of CTCF in the nuclear matrix. Collectively, our data reveal that SATB1 constrains chromatin topology surrounding CTCF-binding sites by tethering CTCF to the nuclear matrix, and suggest that the functional interplay between SATB1 and CTCF contributes to 3D genome organization.
2023-03-05 | GSE224729 | GEO
Project description:Spatial genome organization is critical for precise gene regulation during development. Special AT-rich sequence binding protein 1 (SATB1) has long been proposed to act as a global chromatin loop organizer in T cells. However, the exact functions of SATB1 in genome organization remain elusive. Here we show that the depletion of SATB1 in human and murine T cells led to transcriptional dysregulation for genes involved in T cell activation, as well as alterations of 3D genome architecture at multiple scales, including the A/B compartment, topologically associating domains (TADs), and loops. Importantly, SATB1 extensively colocalizes with CTCF throughout the genome. Depletion of SATB1 led to increased chromatin contacts among and across the SATB1/CTCF co-occupied sites, thereby affecting the transcription of critical genes involved in T cell activation. The loss of SATB1 did not affect the genome-wide occupancy of CTCF, but significantly reduced the retention of CTCF in the nuclear matrix. Collectively, our data reveal that SATB1 constrains chromatin topology surrounding CTCF-binding sites by tethering CTCF to the nuclear matrix, and suggest that the functional interplay between SATB1 and CTCF contributes to 3D genome organization.
2023-03-05 | GSE224728 | GEO
Project description:Catalytic activity of the ISWI family of remodelers is critical for nucleosomal organization and transcription factor binding, including the insulator protein CTCF. To define which subcomplex mediates these diverse functions we phenotyped a panel of isogenic mouse stem cell lines each lacking one of six ISWI accessory subunits. Individual deletions of either CERF, RSF1, ACF, WICH or NoRC subcomplexes only moderately affect the chromatin landscape, while removal of the NURF-specific subunit BPTF leads to drastic reduction in chromatin accessibility and Snf2h ATPase localization around CTCF sites. While this reduces distances to the adjacent nucleosomes it only modestly impacts CTCF binding itself. In absence of accessibility, the insulator function of CTCF is nevertheless impaired resulting in lower occupancy of cohesin and cohesin-loading factors, and reduced insulation at these sites, highlighting the need of NURF-mediated remodeling for open chromatin and proper CTCF function. Our comprehensive analysis reveals a specific role for NURF in mediating Snf2h localization and chromatin opening at bound CTCF sites showing that local accessibility is critical for cohesin binding and insulator function.
2024-03-13 | PXD042945 | Pride
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
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 | GSE164213 | GEO
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 | GSE164212 | GEO
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
Project description:How distal regulatory elements regulate gene transcription and chromatin topology is not clearly defined, yet these processes are intimately linked to cell lineage specification during development. Through allele-specific genome editing and chromatin interaction analysis of the Sox2 locus in mouse embryonic stem cells, we found a striking decoupling of transcriptional control and chromatin architecture. We trace nearly all Sox2 transcriptional activation to a small number of key transcription factor binding sites, whose deletion has no effect on promoter-enhancer interaction frequencies or topological domain organization. Local chromatin architecture maintenance, including at the topologically associating domain (TAD) boundary downstream of the Sox2 enhancer, is conversely widely distributed over multiple transcription factor bound regions and maintained in a CTCF independent manner. Furthermore, disruption of promoter-enhancer interactions via induced ectopic chromatin loop formation has no effect on Sox2 expression. These findings indicate many transcription factors are involved in modulating chromatin architecture independently from CTCF.
2022-02-04 | GSE195906 | GEO