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CTCF是一个依赖DNA张力的障碍来对黏连蛋白介导的环挤压起作用
2023-04-25 10:55

奥地利维也纳生物中心Jan-Michael Peters等研究人员合作发现,CTCF是一个依赖DNA张力的障碍来对黏连蛋白介导的环挤压起作用。2023年4月19日,国际知名学术期刊《自然》在线发表了这一成果。

研究人员表示,在真核生物中,基因组DNA被协同蛋白挤压成环。通过抑制这一过程,DNA结合蛋白CCCTC结合因子(CTCF)产生了拓扑关联域(TAD),在发育和疾病过程中对基因调节和重组有重要作用。目前还不清楚CTCF是如何建立TAD边界的,以及这些边界在多大程度上可以渗透到黏连蛋白中。

为了解决这些问题,研究人员在体外可视化了单个CTCF和黏连蛋白分子在DNA上的相互作用。结果表明,CTCF足以阻断扩散的黏连蛋白,这可能反映了粘连的粘连蛋白是如何在TAD边界聚集的,同时也足以阻断环挤出的粘连蛋白,从而反映了CTCF是如何建立TAD边界的。CTCF的功能是不对称的,正如预测的那样;然而,CTCF依赖于DNA张力。此外,CTCF通过改变其方向和诱导环收缩来调节粘连蛋白的环挤压活动。

这些数据表明,CTCF并不像以前所假设的那样,仅仅是对黏连蛋白介导的环挤压的一个障碍,而是这个过程的一个积极的调节器,据此,TAD边界的渗透性可以被DNA张力所调节。这些结果揭示了CTCF如何控制环挤压和基因组结构的机制原理。

附:英文原文

Title: CTCF is a DNA-tension-dependent barrier to cohesin-mediated loop extrusion

Author: Davidson, Iain F., Barth, Roman, Zaczek, Maciej, van der Torre, Jaco, Tang, Wen, Nagasaka, Kota, Janissen, Richard, Kerssemakers, Jacob, Wutz, Gordana, Dekker, Cees, Peters, Jan-Michael

Issue&Volume: 2023-04-19

Abstract: In eukaryotes, genomic DNA is extruded into loops by cohesin1. By restraining this process, the DNA-binding protein CCCTC-binding factor (CTCF) generates topologically associating domains (TADs)2,3 that have important roles in gene regulation and recombination during development and disease1,4,5,6,7. How CTCF establishes TAD boundaries and to what extent these are permeable to cohesin is unclear8. Here, to address these questions, we visualize interactions of single CTCF and cohesin molecules on DNA in vitro. We show that CTCF is sufficient to block diffusing cohesin, possibly reflecting how cohesive cohesin accumulates at TAD boundaries, and is also sufficient to block loop-extruding cohesin, reflecting how CTCF establishes TAD boundaries. CTCF functions asymmetrically, as predicted; however, CTCF is dependent on DNA tension. Moreover, CTCF regulates cohesin’s loop-extrusion activity by changing its direction and by inducing loop shrinkage. Our data indicate that CTCF is not, as previously assumed, simply a barrier to cohesin-mediated loop extrusion but is an active regulator of this process, whereby the permeability of TAD boundaries can be modulated by DNA tension. These results reveal mechanistic principles of how CTCF controls loop extrusion and genome architecture.

DOI: 10.1038/s41586-023-05961-5

Source: https://www.nature.com/articles/s41586-023-05961-5

Nature:《自然》,创刊于1869年。隶属于施普林格·自然出版集团,最新IF:69.504
官方网址:http://www.nature.com/
投稿链接:http://www.nature.com/authors/submit_manuscript.html


本期文章:《自然》:Online/在线发表

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