Abstract
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.
Highlights
CCCTC-binding factor (CTCF) is a highly conserved zinc finger–containing transcription factor known as “the master weaver of the genome” [1]
We found that acute CTCF depletion directly altered genomewide chromatin accessibility
We confirmed that CTCF was efficiently degraded by immunoblotting three single-cell derived clones treated with IAA for 24 h (Fig. 1B and Additional file 1: Fig. S1A), similar to our previous observation at 48 h [19]
Summary
CCCTC-binding factor (CTCF) is a highly conserved zinc finger–containing transcription factor known as “the master weaver of the genome” [1]. It is the most extensively studied regulator of three-dimensional (3D) chromatin architecture. CTCF-binding occupancy is highly enriched at many known chromatin architecture elements, including chromatin loop anchors and topologically associated domain (TAD) boundaries [5, 6]. 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. Acute depletion of CTCF globally reduces chromatin interactions but does not significantly alter transcription
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