Cohesin structures the genome through the formation of chromatin loops and by holding together the sister chromatids. The acetylation of cohesin’s SMC3 subunit is a dynamic process that involves the acetyltransferase ESCO1 and deacetylase HDAC8. Here we show that this cohesin acetylation cycle controls the three-dimensional genome in human cells. ESCO1 restricts the length of chromatin loops, and of architectural stripes emanating from CTCF sites. HDAC8 conversely promotes the extension of such loops and stripes. This role in controlling loop length turns out to be distinct from the canonical role of cohesin acetylation that protects against WAPL-mediated DNA release. We reveal that acetylation controls the interaction of cohesin with PDS5A to restrict chromatin loop length. Our data support a model in which this PDS5A-bound state acts as a brake that enables the pausing and restart of loop enlargement. The cohesin acetylation cycle hereby provides punctuation in the process of genome folding.

粘连蛋白通过形成染色质环并将姐妹染色单体结合在一起来构建基因组。粘连蛋白 SMC3 亚基的乙酰化是一个动态过程，涉及乙酰转移酶 ESCO1 和脱乙酰酶 HDAC8。在这里，我们证明这种粘连蛋白乙酰化循环控制着人类细胞中的三维基因组。 ESCO1 限制染色质环的长度以及来自 CTCF 位点的结构条纹的长度。 HDAC8 相反地促进此类环和条的延伸。这种控制环长度的作用与粘连蛋白乙酰化的典型作用不同，粘连蛋白乙酰化防止 WAPL 介导的 DNA 释放。我们发现乙酰化控制粘连蛋白与 PDS5A 的相互作用，从而限制染色质环长度。我们的数据支持一个模型，其中 PDS5A 结合状态充当制动器，能够暂停和重新启动循环放大。粘连蛋白乙酰化循环因此在基因组折叠过程中提供标点符号。