2023年9月4日，《自然—遗传学》杂志在线发表了中国科学院深圳先进技术研究院合成生物学研究所甘海云课题组的最新成果。该研究发现，亲本组蛋白的对称遗传有助于在分化过程中保护小鼠胚胎干细胞的命运。

研究人员发现Mcm2突变或Pole3缺失的小鼠胚胎干细胞（ESC）显示出异常的组蛋白景观，并损害了神经分化。Mcm2组蛋白结合域突变会导致胚胎植入前发育缺陷和胚胎死亡。亲本组蛋白偏向转移的ESC表现出更高的表观遗传异质性，在调控分化基因的基因组位点上显示出组蛋白变体H3.3和H3K27me3模式的改变。这些研究结果表明，H3.3的滞后链模式导致了H3K27me3在Mcm2-2A ESC中的重新分布。研究人员证明，对称的亲本组蛋白富集到姐妹染色单体有助于细胞分化和发育。

据介绍，亲本组蛋白是翻译后修饰的载体，它们均匀地沉积在姐妹染色单体的复制DNA上，这一过程依赖于DNA螺旋酶的Mcm2亚基和前导链DNA聚合酶的Pole3亚基。亲本组蛋白传播的生物学意义仍不清楚。

附：英文原文

Title: Symmetric inheritance of parental histones contributes to safeguarding the fate of mouse embryonic stem cells during differentiation

Author: Wen, Qing, Zhou, Jiaqi, Tian, Congcong, Li, Xinran, Song, Guibing, Gao, Yuan, Sun, Yaping, Ma, Chiyuan, Yao, Sitong, Liang, Xiaoyan, Kang, Xing, Wang, Nan, Yao, Yuan, Wang, Hongbao, Liang, Xiaohuan, Tang, Jialin, Offer, Steven M., Lei, Xiaohua, Yu, Chuanhe, Liu, Xiangyu, Liu, Zichuan, Wang, Zhiquan, Gan, Haiyun

Issue&Volume: 2023-09-04

Abstract: Parental histones, the carriers of posttranslational modifications, are deposited evenly onto the replicating DNA of sister chromatids in a process dependent on the Mcm2 subunit of DNA helicase and the Pole3 subunit of leading-strand DNA polymerase. The biological significance of parental histone propagation remains unclear. Here we show that Mcm2-mutated or Pole3-deleted mouse embryonic stem cells (ESCs) display aberrant histone landscapes and impaired neural differentiation. Mutation of the Mcm2 histone-binding domain causes defects in pre-implantation development and embryonic lethality. ESCs with biased parental histone transfer exhibit increased epigenetic heterogeneity, showing altered histone variant H3.3 and H3K27me3 patterning at genomic sites regulating differentiation genes. Our results indicate that the lagging strand pattern of H3.3 leads to the redistribution of H3K27me3 in Mcm2-2A ESCs. We demonstrate that symmetric parental histone deposition to sister chromatids contributes to cellular differentiation and development.

DOI: 10.1038/s41588-023-01477-w

Source: https://www.nature.com/articles/s41588-023-01477-w