CTCF coordinates cell fate specification via orchestrating regulatory hubs with pioneer transcription factors
Yuting Liu,
Xin Wan,
Hu Li,
Yingxi Chen,
Xiaodi Hu,
Hebing Chen,
Dahai Zhu,
Cheng Li,
Yong Zhang
Affiliations
Yuting Liu
School of Life Sciences, Center for Bioinformatics, Center for Statistical Science, Peking University, Beijing 100871, China
Xin Wan
State Key Laboratory of Complex Severe and Rare Disease, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences and School of Basic Medicine, Peking Union Medical College, 5 Dong Dan San Tiao, Beijing 100005, China
Hu Li
Bioland Laboratory (Guangzhou Regenerative Medicine and Health Guangdong Laboratory), Guangzhou 510320, China
Yingxi Chen
State Key Laboratory of Complex Severe and Rare Disease, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences and School of Basic Medicine, Peking Union Medical College, 5 Dong Dan San Tiao, Beijing 100005, China
Xiaodi Hu
State Key Laboratory of Complex Severe and Rare Disease, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences and School of Basic Medicine, Peking Union Medical College, 5 Dong Dan San Tiao, Beijing 100005, China
Hebing Chen
Institute of Health Service and Transfusion Medicine, Taiping Road 27TH, Haidian District, Beijing 100850, China
Dahai Zhu
State Key Laboratory of Complex Severe and Rare Disease, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences and School of Basic Medicine, Peking Union Medical College, 5 Dong Dan San Tiao, Beijing 100005, China; Bioland Laboratory (Guangzhou Regenerative Medicine and Health Guangdong Laboratory), Guangzhou 510320, China; Corresponding author
Cheng Li
School of Life Sciences, Center for Bioinformatics, Center for Statistical Science, Peking University, Beijing 100871, China; Corresponding author
Yong Zhang
State Key Laboratory of Complex Severe and Rare Disease, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences and School of Basic Medicine, Peking Union Medical College, 5 Dong Dan San Tiao, Beijing 100005, China; Bioland Laboratory (Guangzhou Regenerative Medicine and Health Guangdong Laboratory), Guangzhou 510320, China; Corresponding author
Summary: CCCTC-binding factor (CTCF), a ubiquitously expressed architectural protein, has emerged as a key regulator of cell identity gene transcription. However, the precise molecular mechanism underlying specialized functions of CTCF remains elusive. Here, we investigate the mechanism through integrative analyses of primary hepatocytes, myocytes, and B cells from mouse and human. We demonstrate that CTCF cooperates with lineage-specific pioneer transcription factors (TFs), including MyoD, FOXA, and PU.1, to control cell identity at 1D and 3D levels. At the 1D level, pioneer TFs facilitate lineage-specific CTCF occupancy via opening chromatin. At the 3D level, CTCF and pioneer TFs form regulatory hubs to govern the expression of cell identity genes. This mechanism is validated using MyoD-null mice, CTCF knockout mice, and CRISPR editing during myogenic differentiation. Collectively, these findings uncover a general mechanism whereby CTCF acts as a cell identity cofactor to control cell identity genes via orchestrating regulatory hubs with pioneer TFs.
