Department of Molecular Biology, Massachusetts General Hospital, Boston, MA 02114, USA; Department of Genetics, Harvard Medical School, Boston, MA 02114, USA.
Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA 02115, USA; Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA 02115, USA.
Mol Cell. 2021 May 6;81(9):1970-1987.e9. doi: 10.1016/j.molcel.2021.02.031. Epub 2021 Mar 15.
Depletion of architectural factors globally alters chromatin structure but only modestly affects gene expression. We revisit the structure-function relationship using the inactive X chromosome (Xi) as a model. We investigate cohesin imbalances by forcing its depletion or retention using degron-tagged RAD21 (cohesin subunit) or WAPL (cohesin release factor). Cohesin loss disrupts the Xi superstructure, unveiling superloops between escapee genes with minimal effect on gene repression. By contrast, forced cohesin retention markedly affects Xi superstructure, compromises spreading of Xist RNA-Polycomb complexes, and attenuates Xi silencing. Effects are greatest at distal chromosomal ends, where looping contacts with the Xist locus are weakened. Surprisingly, cohesin loss creates an Xi superloop, and cohesin retention creates Xi megadomains on the active X chromosome. Across the genome, a proper cohesin balance protects against aberrant inter-chromosomal interactions and tempers Polycomb-mediated repression. We conclude that a balance of cohesin eviction and retention regulates X inactivation and inter-chromosomal interactions across the genome.
结构因子的耗竭会全局改变染色质结构，但仅对基因表达产生适度影响。我们使用失活 X 染色体 (Xi) 作为模型，重新研究了结构-功能关系。我们通过使用带有降解标签的 RAD21（黏连蛋白亚基）或 WAPL（黏连蛋白释放因子）来强制耗尽或保留黏连蛋白，从而研究黏连蛋白的失衡。黏连蛋白的缺失破坏了 Xi 的超结构，揭示了逃逸基因之间的超级环，对基因抑制的影响最小。相比之下，强制保留黏连蛋白会显著影响 Xi 的超结构，损害 Xist RNA-多梳复合物的扩散，并减弱 Xi 的沉默。这种影响在染色体末端最大，那里与 Xist 基因座的环化接触减弱。令人惊讶的是，黏连蛋白的缺失会在 X 染色体上形成 Xi 超环，而黏连蛋白的保留则会形成 Xi 巨域。在整个基因组中，适当的黏连蛋白平衡可以防止异常的染色体间相互作用，并缓和多梳介导的抑制。我们得出结论，黏连蛋白的驱逐和保留的平衡调节 X 染色体失活和整个基因组的染色体间相互作用。
