期刊
NATURE GENETICS
卷 52, 期 7, 页码 655-+出版社
NATURE PORTFOLIO
DOI: 10.1038/s41588-020-0643-0
关键词
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资金
- RNA-MAPS project [ERC-2011-AdG-294653-RNA-MAPS]
- European Research Council under the 7th Framework Programme FP7/2007-2013 (ERC Synergy Grant 4D-Genome) [609989]
- Ministerio de Educacion y Ciencia [SAF.2012-37167, BFU2017-85926-P]
- AGAUR
- Marato TV3 [201611]
- Deutsche Forschungsgemeinschaft [SFB860, SPP1935, EXC 2067/1-390729940]
- European Research Council (advanced investigator grant TRANSREGULON) [693023]
- Volkswagen Foundation
- Marie Sklodowska-Curie fellowship (H2020-MSCA-IF-2016, miRStem)
- Fundacion Cientifica de la Asociacion Espanola Contra el Cancer
- Juan de la Cierva postdoctoral fellowship (MINECO) [FJCI-2014-22946]
- Secretaria d'Universitats i Recerca del Departament d'Empresa i Coneixement (Generalitat de Catalunya) [2017FI_B00722]
- European Social Fund (ESF)
- Netherlands Organisation for Scientific Research Veni fellowship [91617114]
- Erasmus MC Fellowship
- 'Centro de Excelencia Severo Ochoa 2013-2017', the Spanish Ministry of Science and Innovation [SEV-20120208]
- CERCA Program Generalitat de Catalunya
- Spanish Ministry of Science and Innovation through the Instituto de Salud Carlos III
- Generalitat de Catalunya through Departament de Salut
- European Regional Development Fund (ERDF)
- Generalitat de Catalunya through Departament d'Empresa i Coneixement
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.
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