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CTCF is dispensable for immune cell transdifferentiation but facilitates an acute inflammatory response.
Nature Genetics ( IF 31.7 ) Pub Date : 2020-06-08 , DOI: 10.1038/s41588-020-0643-0
Grégoire Stik 1 , Enrique Vidal 1 , Mercedes Barrero 1 , Sergi Cuartero 1, 2 , Maria Vila-Casadesús 1 , Julen Mendieta-Esteban 3 , Tian V Tian 1, 4 , Jinmi Choi 5 , Clara Berenguer 1, 2 , Amaya Abad 1 , Beatrice Borsari 1 , François le Dily 1 , Patrick Cramer 5 , Marc A Marti-Renom 1, 3, 6 , Ralph Stadhouders 7, 8 , Thomas Graf 1, 9
Affiliation  

Three-dimensional organization of the genome is important for transcriptional regulation1,2,3,4,5,6,7. In mammals, CTCF and the cohesin complex create submegabase structures with elevated internal chromatin contact frequencies, called topologically associating domains (TADs)8,9,10,11,12. Although TADs can contribute to transcriptional regulation, ablation of TAD organization by disrupting CTCF or the cohesin complex causes modest gene expression changes13,14,15,16. 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.



中文翻译:

CTCF对于免疫细胞转分化是必不可少的,但有助于急性炎症反应。

基因组的三维组织对于转录调节1,2,3,4,5,6,7很重要。在哺乳动物中,CTCF和黏附蛋白复合物创建了具有较高内部染色质接触频率的亚兆碱基结构,称为拓扑关联域(TADs)8,9,10,11,12。尽管TADs可以促进转录调控,但通过破坏CTCF或粘着蛋白复合物来消融TAD的组织会引起适度的基因表达变化13,14,15,16。相反,CTCF是细胞周期调控17,胚胎发育和各种成年细胞类型形成所需的18。。为了解开CTCF在细胞状态转换和细胞增殖中的作用,我们研究了在人类白血病B细胞向巨噬细胞转化(细胞分裂最少)过程中CTCF耗竭的影响。CTCF消耗会破坏TAD的组织,但不会破坏细胞的转分化。相反,在暴露于内毒素后,诱导巨噬细胞中的CTCF消耗减弱了炎症基因的全面上调。我们的结果表明,功能性细胞命运转换并非严格要求依赖CTCF的基因组拓扑结构,而是有助于快速有效地响应外部刺激。

更新日期:2020-06-08
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