研究揭示CTCF對於免疫細胞轉分化和激活的影響
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小柯機器人發布時間：2020/6/11 11:21:04
近日，西班牙巴塞隆納科技學院 Thomas Graf、Grégoire Stik、荷蘭伊拉斯姆斯大學Ralph Stadhouders等研究人員發現，CTCF對於免疫細胞轉分化非必需，但可促進急性炎症反應。這一研究成果於2020年6月8日在線發表在《自然—遺傳學》上。
研究人員表示，基因組的三維組織對於轉錄調控很重要。在哺乳動物中，CTCF和cohesin複合物會形成內部染色質接觸頻率升高的亞結構，稱為拓撲關聯域（TAD）。儘管TAD可以促進轉錄調控，但通過破壞CTCF或cohesin複合物來消除TAD結構會引起一定程度的基因表達變化。相反，CTCF是細胞周期調控、胚胎發育和各種成年細胞類型形成所必需的。
為了解開CTCF在細胞狀態轉變和細胞增殖中的作用，研究人員報導了在人類白血病B細胞向巨噬細胞轉化（細胞分裂發生得最少）過程中CTCF敲低的影響。CTCF敲低會破壞TAD的組織，但不會破壞細胞的轉分化。相反，在暴露於內毒素後，誘導巨噬細胞中的CTCF消耗減弱了炎症基因的全面上調。這些結果表明，功能性細胞命運轉換並非嚴格要求依賴CTCF的基因組拓撲結構，而是有助於快速有效地響應外部刺激。
附：英文原文
Title: CTCF is dispensable for immune cell transdifferentiation but facilitates an acute inflammatory response
Author: Grgoire Stik, Enrique Vidal, Mercedes Barrero, Sergi Cuartero, Maria Vila-Casadess, Julen Mendieta-Esteban, Tian V. Tian, Jinmi Choi, Clara Berenguer, Amaya Abad, Beatrice Borsari, Franois le Dily, Patrick Cramer, Marc A. Marti-Renom, Ralph Stadhouders, Thomas Graf
Issue&Volume: 2020-06-08
Abstract: 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.
DOI: 10.1038/s41588-020-0643-0
Source: https://www.nature.com/articles/s41588-020-0643-0