Acute depletion of CTCF rewires genome-wide chromatin accessibility
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA641828 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR12089621_1.fastq.gz | Fastqsanger.gz | |||
| SRR12089621_2.fastq.gz | Fastqsanger.gz | |||
| SRR12089622_1.fastq.gz | Fastqsanger.gz | |||
| SRR12089622_2.fastq.gz | Fastqsanger.gz | |||
| SRR12089623_1.fastq.gz | Fastqsanger.gz |
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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: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
Project description:BackgroundThe 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.ResultsHere, we systematically integrate multi-omics data including ATAC-seq, RNA-seq, WGBS, Hi-C, Cut&Run, and CRISPR-Cas9 survival dropout screens, and time-solved deep proteomic and phosphoproteomic analyses in cells carrying auxin-induced degron at endogenous CTCF locus. Acute CTCF protein degradation markedly rewires genome-wide chromatin accessibility. Increased accessible chromatin regions are frequently located adjacent to CTCF-binding sites at promoter regions and insulator sites associated with enhanced transcription of nearby genes. In addition, we use CTCF-associated multi-omics data to establish a combinatorial data analysis pipeline to discover CTCF co-regulatory partners. We successfully identify 40 candidates, including multiple established partners. Interestingly, many CTCF co-regulators that have alterations of their respective downstream gene expression do not show changes of their own 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.ConclusionsThis study highlights that CTCF loss rewires genome-wide chromatin accessibility, which plays a critical role in transcriptional regulation.
| S-EPMC8386078 | biostudies-literature
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:In human cells, CTCF’s role in genomic organization and global transcription regulation is less clearly defined due to the lack of available tools to efficiently deplete CTCF. Here, we used an auxin-inducible degron system to conditionally deplete CTCF in a human B-cell lymphoblastic leukemia (B-ALL) cell line, SEM. Cut & Run ChIP-seq showed acute depletion of CTCF disrupted the direct interaction between the MYC promoter and its distal enhancer cluster residing ~1.8 Mb downstream.
2019-05-14 | GSE126619 | GEO
Project description:Acute depletion of CTCF directly affects MYC regulation through loss of enhancer–promoter looping
| PRJNA496496 | ENA
Project description:Acute depletion of CTCF directly affects MYC regulation through loss of enhancer–promoter looping
| PRJNA577635 | ENA
Project description:Acute depletion of CTCF directly affects MYC regulation through loss of enhancer–promoter looping
| PRJNA494510 | ENA
Project description:Acute depletion of CTCF directly affects MYC regulation through loss of enhancer-promoter looping
| PRJNA522734 | ENA
Project description:Efficient treatment of Acute Myeloid Leukemia (AML) patients remains a challenge despite recent advances. Here using a CRISPRi screen targeting chromatin factors, we identified BPTF as an essential regulator of AML cell survival. We demonstrate that BPTF forms an alternative NURF chromatin remodeling complex with SMARCA5 and BAP18, which regulates the accessibility of a large set of insulator regions in leukemic cells. This ensures efficient CTCF binding and boundary formation between topologically associated domains that is essential for maintaining the leukemic transcriptional programs. We also demonstrate that the well-studied PHD2-BROMO chromatin reader modules of BPTF, while contributing to complex recruitment to chromatin, are dispensable for leukemic cell growth. Taken together, our results uncover how the alternative NURF complex contributes to leukemia and provide a rationale for its targeting in AML.
2023-11-12 | PXD044656 | Pride