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Epigenomics; Functional genomics; Gene regulation; Immunology
Abstract:
Lettershttps://doi.org/10.1038/s41588-020-0643-01Centre for Genomic Regulation (CRG) and Institute of Science and Technology (BIST), Barcelona, Spain. 2Josep Carreras Leukaemia Research Institute (IJC), Barcelona, Spain. 3CNAG-CRG, Centre for Genomic Regulation (CRG), Barcelona Institute of Science and Technology (BIST), Barcelona, Spain. 4Vall d’Hebron Institute of Oncology (VHIO), Barcelona, Spain. 5Max Planck Institute for Biophysical Chemistry, Göttingen, Germany. 6ICREA, Barcelona, Spain. 7Department of Pulmonary Medicine, Erasmus MC, Rotterdam, the Netherlands. 8Department of Cell Biology, Erasmus MC, Rotterdam, the Netherlands. 9Universitat Pompeu Fabra (UPF), Barcelona, Spain. ✉e-mail: gregoire.stik@crg.eu; r.stadhouders@erasmusmc.nl; thomas.graf@crg.euThree-dimensional organization of the genome is important for transcriptional regulation1–7. In mammals, CTCF and the cohesin complex create submegabase structures with ele-vated internal chromatin contact frequencies, called topo-logically associating domains (TADs)8–12. Although TADs can contribute to transcriptional regulation, ablation of TAD organization by disrupting CTCF or the cohesin com-plex causes modest gene expression changes13–16. In con-trast, 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 pro-liferation, 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 orga-nization but not cell transdifferentiation. In contrast, CTCF depletion in induced macrophages impairs the full-blown upregulation of inflammatory genes after exposure to endo-toxin. Our results demonstrate that CTCF-dependent genome topology is not strictly required for a functional cell-fate con-version but facilitates a rapid and efficient response to an external stimulus.
