Acute depletion of CTCF rewires genome-wide chromatin accessibility

Genome Biology

Mohamed Nadhir Djekidel¹  Wojciech Rosikiewicz¹  Beisi Xu¹  Yiping Fan¹  Junmin Peng²  Hong Wang²  Ying Shao³  Mingming Niu⁴  Rui Lu⁵  Chunliang Li⁶  Judith Hyle⁶  Yang Zhang⁶  Shaela Wright⁶ 

[1] Center for Applied Bioinformatics, St. Jude Children’s Research Hospital, 262 Danny Thomas Place, 38105, Memphis, TN, USA;Center for Proteomics and Metabolomics, St. Jude Children’s Research Hospital, 262 Danny Thomas Place, 38105, Memphis, TN, USA;Departments of Structural Biology and Developmental Neurobiology, St. Jude Children’s Research Hospital, 262 Danny Thomas Place, 38105, Memphis, TN, USA;Computational Biology, St. Jude Children’s Research Hospital, 262 Danny Thomas Place, 38105, Memphis, TN, USA;Departments of Structural Biology and Developmental Neurobiology, St. Jude Children’s Research Hospital, 262 Danny Thomas Place, 38105, Memphis, TN, USA;Division of Hematology/Oncology, University of Alabama at Birmingham, 1824 6th Ave S WTI 510G, 35294, Birmingham, AL, USA;O’Neal Comprehensive Cancer Center, University of Alabama at Birmingham, 1824 6th Ave S WTI 510G, 35294, Birmingham, AL, USA;Tumor Cell Biology, St. Jude Children’s Research Hospital, 262 Danny Thomas Place, 38105, Memphis, TN, USA;

关键词: ATAC-seq;    Auxin-induced degron;    Chromatin accessibility;    CTCF;    Transcription factor;    Proteomics;    Phosphoproteomics;   

DOI  :  10.1186/s13059-021-02466-0

来源: Springer

【 摘 要 】

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.

【 授权许可】

CC BY