丹麦哥本哈根大学Anja Groth等研究人员合作发现,亲本组蛋白的对称遗传制约着表观基因组的维持和胚胎干细胞的特性。这一研究成果于2023年9月4日在线发表在国际学术期刊《自然—遗传学》上。
研究人员展示了DNA复制过程中组蛋白信息的传递可维持表观基因组的保真度和胚胎干细胞的可塑性。在MCM2-2A突变体中,亲本组蛋白H3-H4的不对称分离损害了组蛋白修饰的有丝分裂遗传,并全面改变了表观基因组。这包括抑制性修饰的广泛虚假积累,表明表观遗传噪音增加。此外,重复序列上H3K9me3的缺失会导致抑制作用减弱,二价启动子上H3K27me3的重新分布与发育基因的错误表达有关。MCM2-2A突变对整个细胞周期中细胞状态的动态转变提出了挑战,增强了初始多能性,并降低了G1期的谱系活化。
此外,发育能力减弱,这与多能性退出受损有关。总之,这表明组蛋白修饰的表观遗传能够维持正确平衡和动态的染色质景观,从而支持哺乳动物细胞的分化。
据悉,在复制过程中,修饰过的亲本组蛋白会对称地分离到子DNA链上,并通过有丝分裂遗传下去。这将如何维持表观基因组和细胞特性仍是未知数。
附:英文原文
Title: Symmetric inheritance of parental histones governs epigenome maintenance and embryonic stem cell identity
Author: Wenger, Alice, Biran, Alva, Alcaraz, Nicolas, Red-Riveiro, Alba, Sell, Annika Charlotte, Krautz, Robert, Flury, Valentin, Revern-Gmez, Nazaret, Solis-Mezarino, Victor, Vlker-Albert, Moritz, Imhof, Axel, Andersson, Robin, Brickman, Joshua M., Groth, Anja
Issue&Volume: 2023-09-04
Abstract: Modified parental histones are segregated symmetrically to daughter DNA strands during replication and can be inherited through mitosis. How this may sustain the epigenome and cell identity remains unknown. Here we show that transmission of histone-based information during DNA replication maintains epigenome fidelity and embryonic stem cell plasticity. Asymmetric segregation of parental histones H3–H4 in MCM2-2A mutants compromised mitotic inheritance of histone modifications and globally altered the epigenome. This included widespread spurious deposition of repressive modifications, suggesting elevated epigenetic noise. Moreover, H3K9me3 loss at repeats caused derepression and H3K27me3 redistribution across bivalent promoters correlated with misexpression of developmental genes. MCM2-2A mutation challenged dynamic transitions in cellular states across the cell cycle, enhancing nave pluripotency and reducing lineage priming in G1. Furthermore, developmental competence was diminished, correlating with impaired exit from pluripotency. Collectively, this argues that epigenetic inheritance of histone modifications maintains a correctly balanced and dynamic chromatin landscape able to support mammalian cell differentiation.
DOI: 10.1038/s41588-023-01476-x
Source: https://www.nature.com/articles/s41588-023-01476-x
Nature Genetics:《自然—遗传学》,创刊于1992年。隶属于施普林格·自然出版集团,最新IF:41.307
官方网址:https://www.nature.com/ng/
投稿链接:https://mts-ng.nature.com/cgi-bin/main.plex