TY - JOUR
T1 - CTCF coordinates cell fate specification via orchestrating regulatory hubs with pioneer transcription factors
AU - Liu, Yuting
AU - Wan, Xin
AU - Li, Hu
AU - Chen, Yingxi
AU - Hu, Xiaodi
AU - Chen, Hebing
AU - Zhu, Dahai
AU - Li, Cheng
AU - Zhang, Yong
N1 - Publisher Copyright:
© 2023 The Authors
PY - 2023/10/31
Y1 - 2023/10/31
N2 - 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.
AB - 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.
KW - 3D genome
KW - CP: Molecular biology
KW - CP: Stem cell research
KW - CRISPR editing
KW - CTCF
KW - MyoD
KW - cell identity
KW - pioneer transcription factor
KW - regulatory hub
UR - http://www.scopus.com/inward/record.url?scp=85174167482&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85174167482&partnerID=8YFLogxK
U2 - 10.1016/j.celrep.2023.113259
DO - 10.1016/j.celrep.2023.113259
M3 - Article
C2 - 37851578
AN - SCOPUS:85174167482
SN - 2211-1247
VL - 42
JO - Cell reports
JF - Cell reports
IS - 10
M1 - 113259
ER -