Loop extrusion by cohesin plays a key role in enhancer-activated gene expression during differentiation
Loop extrusion by cohesin plays a key role in enhancer-activated gene expression during differentiation
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DOI：
10.1101/2023.09.07.556660
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发表时间：
2023-09
期刊：
影响因子：
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通讯作者：
Rosa J. Stolper;Felice H. Tsang;E. Georgiades;Lars L.P. Hansen;D. Downes;Caroline L. Harrold;J. Hughes;Robert A. Beagrie;Benjamin Davies;Mira T. Kassouf;D. Higgs
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文献类型：
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作者：
Rosa J. Stolper;Felice H. Tsang;E. Georgiades;Lars L.P. Hansen;D. Downes;Caroline L. Harrold;J. Hughes;Robert A. Beagrie;Benjamin Davies;Mira T. Kassouf;D. Higgs
增强子及其目标启动子在被激活时通常在物理上非常接近。这种接近性可以用多种机制来解释；最近通过粘连蛋白介导的染色质环挤出。尽管有这个令人信服的假设，粘连蛋白的急性消耗并不会引起基因表达的广泛变化。我们测试了粘连蛋白介导的环挤压对红细胞生成过程中小鼠α珠蛋白位点基因表达的作用。粘连蛋白的急性消耗会下调分化早期而非晚期的α-珠蛋白表达。当在α珠蛋白增强子和启动子之间放置单个或多个CTCF位点时，α基因表达下调。重要的是，CTCF 位点的方向起着关键作用，这表明在这个激活的结构域内，粘连蛋白主要但不完全从增强子易位到启动子。我们发现环挤出确实在分化过程中建立增强子-启动子邻近性和诱导基因的后续表达中发挥重要作用。
Enhancers and their target promoters often come into close physical proximity when activated. This proximity may be explained by a variety of mechanisms; most recently via cohesin-mediated chromatin loop extrusion. Despite this compelling hypothesis, acute depletion of cohesin does not cause widespread changes in gene expression. We have tested the role of cohesin-mediated loop extrusion on gene expression at the mouse alpha-globin locus during erythropoiesis. Acute depletion of cohesin downregulates alpha-globin expression at early but not late stages of differentiation. When single or multiple CTCF sites are placed between the alpha-globin enhancers and promoters, alpha-gene expression is downregulated. Importantly, the orientation of the CTCF site plays a critical role, suggesting that within this activated domain, cohesin predominantly but not exclusively translocates from the enhancers to the promoters. We find that loop extrusion does play an important role in establishing enhancer-promoter proximity and consequent expression of inducible genes during differentiation.