PDS5A and PDS5B differentially affect gene expression without altering cohesin localization across the genome.
PDS5A and PDS5B differentially affect gene expression without altering cohesin localization across the genome.
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DOI：
10.1186/s13072-022-00463-6
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发表时间：
2022-08-19
影响因子：
3.9
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中科院分区：
文献类型：
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粘着蛋白是基因组的重要结构调节因子，调节基因组的三维结构和基因表达。核心粘附素三聚体与各种HEAT重复辅助亚基相互作用，产生不同组成和潜在不同功能的粘附素复合物。两个相互排斥的HEAT重复亚基PDS 5A和PDS 5 B的作用还不清楚。在这里，我们确定PDS 5A和PDS 5 B在小鼠胚胎干细胞（mESC）基因组中具有高度相似的定位模式，并且它们与其他粘着蛋白HEAT重复辅助亚基STAG 1和STAG 2具有很强的重叠。使用CRISPR/Cas9基因组编辑来生成PDS 5A和PDS 5 B的个体稳定敲除系，我们发现一个PDS 5亚基的丢失不会改变另一个PDS 5亚基的分布，也不会改变核心粘附素复合物。PDS 5A和PDS 5 B都是正确基因表达所必需的，但它们对基因靶点的作用仅部分重叠。值得注意的是，尽管所有四种蛋白质的基因组分布重叠，但PDS 5 HEAT重复蛋白质的双重消耗后的基因表达并不完全重叠由STAG HEAT重复蛋白质的双重消耗引起的基因表达变化。此外，PDS 5A和PDS 5 B的双重缺失降低了与NIPBL和WAPL的粘着蛋白缔合，降低了SMC 3乙酰化，并且不改变基因组上粘着蛋白的总体水平。这项工作揭示了PDS 5A和PDS 5 B对于适当的粘附素功能的重要性。任何一个亚基的缺失对整个基因组的粘附蛋白定位几乎没有影响，但PDS 5A和PDS 5 B是基因表达所需的差异。在线版本包含补充材料，可通过10.1186/s13072-022-00463-6获得。
Cohesin is an important structural regulator of the genome, regulating both three-dimensional genome organization and gene expression. The core cohesin trimer interacts with various HEAT repeat accessory subunits, yielding cohesin complexes of distinct compositions and potentially distinct functions. The roles of the two mutually exclusive HEAT repeat subunits PDS5A and PDS5B are not well understood. Here, we determine that PDS5A and PDS5B have highly similar localization patterns across the mouse embryonic stem cell (mESC) genome and they show a strong overlap with other cohesin HEAT repeat accessory subunits, STAG1 and STAG2. Using CRISPR/Cas9 genome editing to generate individual stable knockout lines for PDS5A and PDS5B, we find that loss of one PDS5 subunit does not alter the distribution of the other PDS5 subunit, nor the core cohesin complex. Both PDS5A and PDS5B are required for proper gene expression, yet they display only partially overlapping effects on gene targets. Remarkably, gene expression following dual depletion of the PDS5 HEAT repeat proteins does not completely overlap the gene expression changes caused by dual depletion of the STAG HEAT repeat proteins, despite the overlapping genomic distribution of all four proteins. Furthermore, dual loss of PDS5A and PDS5B decreases cohesin association with NIPBL and WAPL, reduces SMC3 acetylation, and does not alter overall levels of cohesin on the genome. This work reveals the importance of PDS5A and PDS5B for proper cohesin function. Loss of either subunit has little effect on cohesin localization across the genome yet PDS5A and PDS5B are differentially required for gene expression. The online version contains supplementary material available at 10.1186/s13072-022-00463-6.
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DOI：
10.1126/science.abn6583
发表时间：
2022-04-29
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
通讯作者：
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影响因子：
16.8
作者：
Bastie, Nathalie;Chapard, Christophe;Koszul, Romain
通讯作者：
Koszul, Romain
影响因子：
64.5
作者：
Bauer BW;Davidson IF;Canena D;Wutz G;Tang W;Litos G;Horn S;Hinterdorfer P;Peters JM
通讯作者：
Peters JM
影响因子：
64.5
作者：
Dowen JM;Fan ZP;Hnisz D;Ren G;Abraham BJ;Zhang LN;Weintraub AS;Schujiers J;Lee TI;Zhao K;Young RA
通讯作者：
Young RA
影响因子：
5.9
作者：
Dowen, Jill M.;Bilodeau, Steve;Young, Richard A.
通讯作者：
Young, Richard A.