Escobar Thelma M, Yu Jia-Ray, Liu Sanxiong, Lucero Kimberly, Vasilyev Nikita, Nudler Evgeny, Reinberg Danny
Department of Biochemistry and Molecular Pharmacology, New York University Grossman School of Medicine, New York, NY, USA.
Howard Hughes Medical Institute, New York University Grossman School of Medicine, New York, NY, USA.
Sci Adv. 2022 Apr 29;8(17):eabm3945. doi: 10.1126/sciadv.abm3945. Epub 2022 Apr 27.
The epigenetic process safeguards cell identity during cell division through the inheritance of appropriate gene expression profiles. We demonstrated previously that parental nucleosomes are inherited by the same chromatin domains during DNA replication only in the case of repressed chromatin. We now show that this specificity is conveyed by NPM1, a histone H3/H4 chaperone. Proteomic analyses of late S-phase chromatin revealed NPM1 in association with both H3K27me3, an integral component of facultative heterochromatin, and MCM2, an integral component of the DNA replication machinery; moreover, NPM1 interacts directly with PRC2 and with MCM2. Given that NPM1 is essential, the inheritance of repressed chromatin domains was examined anew using mESCs expressing an auxin-degradable version of endogenous NPM1. Upon NPM1 degradation, cells accumulated in the G-S phase of the cell cycle and parental nucleosome inheritance from repressed chromatin domains was markedly compromised. NPM1 chaperone activity may contribute to the integrity of this process as appropriate inheritance required the NPM1 acidic patches.
表观遗传过程通过适当基因表达谱的遗传在细胞分裂过程中保护细胞身份。我们之前证明，仅在抑制性染色质的情况下，亲代核小体在DNA复制过程中由相同的染色质结构域遗传。我们现在表明，这种特异性是由组蛋白H3/H4伴侣NPM1传递的。对S期后期染色质的蛋白质组学分析显示，NPM1与兼性异染色质的一个组成部分H3K27me3以及DNA复制机器的一个组成部分MCM2相关联；此外，NPM1直接与PRC2和MCM2相互作用。鉴于NPM1是必不可少的，使用表达内源性NPM1的生长素可降解版本的小鼠胚胎干细胞重新检查了抑制性染色质结构域的遗传。在NPM1降解后，细胞在细胞周期的G-S期积累，并且来自抑制性染色质结构域的亲代核小体遗传明显受损。NPM1伴侣活性可能有助于该过程的完整性，因为适当的遗传需要NPM1酸性补丁。
