Extensive mutual influences of SMC complexes shape 3D genome folding

Haoyue Zhang, Han Zhao, Lirong Shu, Fuhai Liu, En Lin, Sijian Xia, Baiyue Wang, Manzhu Wang, Fengnian Shan, Yinzhi Lin, Lin Zhang, Yufei Gu, Gerd Blobel
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Abstract

Mammalian genomes are folded by the distinct actions of SMC complexes which include the chromatin loop-extruding cohesin, the sister-chromatid cohesive cohesin, and the mitotic chromosome-associated condensins. While these complexes function at different stages of the cell cycle, they co-exist on chromatin during the G2/M-phase transition, when genome structure undergoes a dramatic reorganization. Yet, how distinct SMC complexes affect each other and how their mutual interplay orchestrates the dynamic folding of 3D genome remains elusive. Here, we engineered all possible cohesin/condensin configurations on mitotic chromosomes to delineate the concerted, mutual influential action of SMC complexes. We find that: (i) The mitotic SMC complex condensin disrupts the focal accumulation of extrusive-cohesin at CTCF binding sites, thereby promoting the disassembly of interphase TADs and chromatin loops during mitotic progression. Conversely, extrusive-cohesin can impair condensin activity and alter mitotic chromosome helicity. (ii) Condensin diminishes cohesive-cohesin focal enrichment and, conversely, cohesive-cohesin can counteract condensin function and impede mitotic chromosome longitudinal shortening. (iii) The co-presence of extrusive- and cohesive-cohesin synergistically antagonizes condensin function and dramatically delays mitotic chromosome condensation. (iv) Extrusive-cohesin positions cohesive-cohesin at CTCF binding sites. However, cohesive-cohesin by itself is insufficient to mediate the formation of TADs or chromatin loop, implying non-overlapping function with extrusive-cohesin. Instead, cohesive-cohesin restricts chromatin loop expansion, potentially by limiting extrusive-cohesin movement. Collectively, our data describe a comprehensive three way interplay among major SMC complexes that dynamically sculpts chromatin architecture during cell cycle progression.
SMC复合物的广泛相互影响塑造了三维基因组折叠
哺乳动物的基因组是在 SMC 复合物的不同作用下折叠的,这些复合物包括染色质环挤出粘合素、姐妹染色质粘合素和有丝分裂染色体相关凝聚素。这些复合体在细胞周期的不同阶段发挥作用,但在基因组结构发生剧烈重组的 G2/M 期转变期间,它们在染色质上共存。然而,不同的 SMC 复合物如何相互影响,以及它们如何相互配合协调三维基因组的动态折叠,至今仍是个谜。在这里,我们设计了有丝分裂染色体上所有可能的凝聚素/凝集素构型,以描述 SMC 复合物的协同、相互影响作用。我们发现(i) 有丝分裂 SMC 复合体凝集素会破坏 CTCF 结合位点上的外切-凝聚素的灶性聚集,从而在有丝分裂过程中促进间期 TAD 和染色质环的解体。相反,挤出粘连蛋白会损害凝集素的活性,改变有丝分裂染色体的螺旋性。(ii) 凝集素可减少内聚凝聚素的富集灶,反之,内聚凝聚素可抵消凝集素的功能,阻碍有丝分裂染色体纵向缩短。(iii) 外向凝聚素和内聚凝聚素的共同存在可协同拮抗凝聚素的功能,并显著延迟有丝分裂染色体的凝聚。(iv) 外生凝聚素将内生凝聚素置于 CTCF 结合位点。然而,内聚凝聚素本身不足以介导 TAD 或染色质环的形成,这意味着它与外聚凝聚素的功能并不重叠。相反,内聚凝聚素可能通过限制外聚凝聚素的运动来限制染色质环的扩展。总之,我们的数据描述了主要 SMC 复合物之间全面的三向相互作用,在细胞周期进展过程中动态地雕刻染色质结构。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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