小柯机器人

美国哥伦比亚大学欧文医学中心Zhiguo Zhang团队近期取得重要工作进展，他们研究发现，亲本H3K9me3在S期的不对称分布抑制L1元件的表达。相关研究成果2023年11月8日在线发表于《自然》杂志上。

据介绍，在真核生物中，重复的DNA序列通过组蛋白H3第9位赖氨酸的三甲基化（H3K9me3）转录沉默。重复元件沉默的缺失会导致基因组不稳定和人类疾病，包括癌症和衰老。尽管H3K9me3在异染色质沉默的建立和维持中的作用已被广泛研究，但亲本H3K9me3在复制DNA链上的分配模式和机制尚不清楚。

研究人员报道了H3K9me3优先转移到复制叉的前导链上，这主要发生在长散布核元件（LINE）反转录转座子（也称为LINE-1或L1）上，理论上，这些反转录转座子与复制叉的运动正向转录。从机制上讲，人类沉默中枢（HUSH）复合物与前导链DNA聚合酶Pol ε相互作用，并有助于H3K9me3的不对称分离。缺乏Pol ε亚基（POLE3和POLE4）或HUSH复合物(MPP8和TASOR)的细胞显示H3K9me3不对称性受损和LINE的表达增加。在表达H3K9me3结合缺陷的MPP8突变体和与Pol ε相互作用减少的TASOR突变体的细胞中也获得了类似的结果。

总之，这些结果揭示，HUSH复合物与Pol ε一起发挥作用，促进正面LINE的H3K9me3不对称分布，从而抑制它们在S期中的表达。

附：英文原文

Title: Asymmetric distribution of parental H3K9me3 in Sphase silences L1 elements

Author: Li, Zhiming, Duan, Shoufu, Hua, Xu, Xu, Xiaowei, Li, Yinglu, Menolfi, Demis, Zhou, Hui, Lu, Chao, Zha, Shan, Goff, Stephen P., Zhang, Zhiguo

Issue&Volume: 2023-11-08

Abstract: In eukaryotes, repetitive DNA sequences are transcriptionally silenced through histone H3 lysine 9 trimethylation (H3K9me3). Loss of silencing of the repeat elements leads to genome instability and human diseases, including cancer and ageing1–3. Although the role of H3K9me3 in the establishment and maintenance of heterochromatin silencing has been extensively studied4–6, the pattern and mechanism that underlie the partitioning of parental H3K9me3 at replicating DNA strands are unknown. Here we report that H3K9me3 is preferentially transferred onto the leading strands of replication forks, which occurs predominantly at long interspersed nuclear element (LINE) retrotransposons (also known as LINE-1s or L1s) that are theoretically transcribed in the head-on direction with replication fork movement. Mechanistically, the human silencing hub (HUSH) complex interacts with the leading-strand DNA polymerase Pol ε and contributes to the asymmetric segregation of H3K9me3. Cells deficient in Pol ε subunits (POLE3 and POLE4) or the HUSH complex (MPP8 and TASOR) show compromised H3K9me3 asymmetry and increased LINE expression. Similar results were obtained in cells expressing a MPP8 mutant defective in H3K9me3 binding and in TASOR mutants with reduced interactions with Pol ε. These results reveal an unexpected mechanism whereby the HUSH complex functions with Pol ε to promote asymmetric H3K9me3 distribution at head-on LINEs to suppress their expression in S phase. The epigenetic modification H3K9me3 is asymmetrically partitioned at long interspersed nuclear element retrotransposons for their silencing in S phase, a newly discovered mechanism that is mediated by the HUSH complex and the DNA polymerase Pol ε.

DOI: 10.1038/s41586-023-06711-3

Source: https://www.nature.com/articles/s41586-023-06711-3

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