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

Stik, Grégoire; Vidal, Enrique; Barrero, Mercedes; Cuartero, Sergi; Vila-Casadesús, Maria; Mendieta Esteban, Julen, 1992-; Tian, Tian V.; Choi, Jinmi; Berenguer, Clara; Abad, Amaya; Borsari, Beatrice, 1992-; Le Dily, François; Cramer, Patrick; Marti-Renom, Marc A.; Stadhouders, Ralph; Graf, T. (Thomas)

doi:http://dx.doi.org/10.1038/s41588-020-0643-0

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

Citation

Stik G, Vidal E, Barrero M, Cuartero S, Vila-Casadesús M, Mendieta-Esteban J, Tian TV, Choi J, Berenguer C, Abad A, Borsari B, le Dily F, Cramer P, Marti-Renom MA, Stadhouders R, Graf T. CTCF is dispensable for immune cell transdifferentiation but facilitates an acute inflammatory response. Nat Genet. 2020; 52(7):655-61. DOI: 10.1038/s41588-020-0643-0

Abstract

Three-dimensional organization of the genome is important for transcriptional regulation1-7. 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 changes13-16. In contrast, CTCF is required for cell cycle regulation17, embryonic development and formation of various adult cell types18. 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.