CTCF coordinates cell fate specification via orchestrating regulatory hubs with pioneer transcription factors

• Published in: Cell reports (Cambridge) 2023-10, Vol.42 (10), p.113259-113259, Article 113259
• Main Authors: Liu, Yuting, Wan, Xin, Li, Hu, Chen, Yingxi, Hu, Xiaodi, Chen, Hebing, Zhu, Dahai, Li, Cheng, Zhang, Yong
• Format: Article
• Language: English
• Subjects: 3D genome; cell identity; CP: Molecular biology; CP: Stem cell research; CRISPR editing; CTCF; MyoD; pioneer transcription factor; regulatory hub
• ISSN: 2211-1247; 2211-1247
• DOI: 10.1016/j.celrep.2023.113259

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. [Display omitted] •CTCF colocalizes with lineage-specific pioneer transcription factors at super-enhancers•CTCF and pioneer transcription factors form regulatory hubs to regulate cell identity genes•MyoD facilitates myocyte-specific CTCF occupancy via opening chromatin•CTCF is required for MyoD function to control muscle cell identity Liu et al. discovered that CTCF, as a cell identify cofactor, regulates cell lineage genes by forming regulatory hubs with lineage-specific pioneer transcription factors, uncovering the mechanism underlying functional specificity of CTCF in cell-fate determination.