CTCF is dispensable for immune cell transdifferentiation but facilitates an acute inflammatory response

• Published in: Nature genetics Vol. 52; no. 7; pp. 655 - 661
• Main Authors: Stik, Grégoire, Vidal, Enrique, Barrero, Mercedes, Cuartero, Sergi, Vila-Casadesús, Maria, Mendieta-Esteban, Julen, Tian, Tian V., Choi, Jinmi, Berenguer, Clara, Abad, Amaya, Borsari, Beatrice, le Dily, François, Cramer, Patrick, Marti-Renom, Marc A., Stadhouders, Ralph, Graf, Thomas
• Format: Journal Article
• Language: English
• Published: New York Nature Publishing Group US 01.07.2020; Nature Publishing Group
• Subjects: 13; 13/31; 38; 45/15; 45/23; 45/43; 45/91; 631/208/177; 631/208/191; 631/208/200; 631/250; Ablation; Agriculture; Animal Genetics and Genomics; Antigens, Differentiation - metabolism; B-Lymphocytes - physiology; Binding sites; Biomedical and Life Sciences; Biomedicine; Cancer Research; CCCTC-Binding Factor - genetics; CCCTC-Binding Factor - physiology; Cell cycle; Cell division; Cell Line, Tumor; Cell proliferation; Cell Proliferation - physiology; Chromatin; Chromatin - physiology; Chromosomes; Cohesin; Conversion; Depletion; Embryogenesis; Embryonic growth stage; Endotoxins; Gene expression; Gene Expression Regulation; Gene Function; Gene regulation; Genomes; Human Genetics; Humans; Immune system; Inflammation; Inflammatory response; Letter; Leukemia; Lymphocytes B; Macrophages; Macrophages - physiology; Molecular Conformation; Myelopoiesis - genetics; Myelopoiesis - physiology; Principal components analysis; Protein Conformation; Topology; Transcription; Transcription factors
• ISSN: 1061-4036; 1546-1718; 1546-1718
• DOI: 10.1038/s41588-020-0643-0

Three-dimensional organization of the genome is important for transcriptional regulation 1 – 7 . In mammals, CTCF and the cohesin complex create submegabase structures with elevated internal chromatin contact frequencies, called topologically associating domains (TADs) 8 – 12 . Although TADs can contribute to transcriptional regulation, ablation of TAD organization by disrupting CTCF or the cohesin complex causes modest gene expression changes 13 – 16 . In contrast, CTCF is required for cell cycle regulation 17 , embryonic development and formation of various adult cell types 18 . To uncouple the role of CTCF in cell-state transitions and cell proliferation, we studied the effect of CTCF depletion during the conversion of human leukemic B cells into macrophages with minimal cell division. CTCF depletion disrupts TAD organization but not cell transdifferentiation. In contrast, CTCF depletion in induced macrophages impairs the full-blown upregulation of inflammatory genes after exposure to endotoxin. Our results demonstrate that CTCF-dependent genome topology is not strictly required for a functional cell-fate conversion but facilitates a rapid and efficient response to an external stimulus. CTCF is dispensable for transdifferentiation of B cells into induced macrophages despite widespread loss of topologically associating domains. CTCF depletion impairs upregulation of inflammatory genes after endotoxin exposure by destabilizing promoter–enhancer interactions.