Acute depletion of CTCF rewires genome-wide chromatin accessibility

• DOI: 10.1186/s13059-021-02466-0
• Publication Date: 2021-08-24T12:03:03Z
• Authors: Beisi Xu; Hong Wang; Shaela Wright; Judith Hyle; Yang Zhang; Ying Shao; Mingming Niu; Yiping Fan; Wojciech Rosikiewicz; Mohamed Nadhir Dj...; Junmin Peng; Rui Lu; Chunliang Li
• Keywords: Proteomics; 0301 basic medicine; CCCTC-Binding Factor; QH301-705.5; QH426-470; 03 medical and health sciences; Cell Line, Tumor; Genetics; Humans; Biology (General); Chromatin accessibility; Binding Sites; Base Sequence; Genome, Human; Research; Reproducibility of Results; ATAC-seq; Genomics; CTCF; Chromatin; Neoplasm Proteins; Gene Expression Regulation; Auxin-induced degron; Transcription factor; Gene Deletion

AbstractBackgroundThe 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.