小柯机器人

美国杜克大学医学院Gang Greg Wang和美国加州大学Jikui Song共同合作，近期取得重要工作进展。他们研究发现，TNRC18参与H3K9me3介导的内源性反转录转座子沉默。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，组蛋白H3第9位赖氨酸的三甲基化（H3K9me3）对调节基因抑制、异染色质形成、细胞命运决定和组织发育至关重要。H3K9me3也为沉默转座元件提供了一种重要的机制。然而，先前的研究表明，经典的H3K9me3“阅读器“（例如，HP1和MPP8）在沉默内源性逆转录病毒（ERV）方面的作用有限，ERV是哺乳动物基因组中的主要转座元件类别之一。

研究人员报道了含有18（TNRC18），一种鲜为人知的染色质调节因子，识别H3K9me3介导ERV类的沉默 I（ERV1）元件，例如LTR12。生化、生物物理和结构研究确定TNRC18的羧基末端溴相邻同源性（BAH）结构域（TNRC18（BAH））是H3K9me3特异性“阅读器“。

此外，TNRC18的氨基末端片段是直接募集共阻遏物（如HDAC–Sin3–NCoR复合物）的平台，从而对H3K9me3标定的ERV进行最佳抑制。破坏TNRC18（BAH）介导的H3K9me3参与的点突变导致小鼠新生儿死亡，并在多种哺乳动物细胞模型中导致ERV的表达降低，从而影响顺式调节元件及基因的表达程序。

总之，研究人员描述了一种新的H3K9me3传感和调节途径，该途径在表观遗传学上使演化上年轻的ERV沉默，并对宿主基因组完整性、转录组调控、免疫和发育产生实质性影响。

附：英文原文

Title: TNRC18 engages H3K9me3 to mediate silencing of endogenous retrotransposons

Author: Zhao, Shuai, Lu, Jiuwei, Pan, Bo, Fan, Huitao, Byrum, Stephanie D., Xu, Chenxi, Kim, Arum, Guo, Yiran, Kanchi, Krishna L., Gong, Weida, Sun, Tongyu, Storey, Aaron J., Burkholder, Nathaniel T., Mackintosh, Samuel G., Kuhlers, Peyton C., Edmondson, Ricky D., Strahl, Brian D., Diao, Yarui, Tackett, Alan J., Raab, Jesse R., Cai, Ling, Song, Jikui, Wang, Gang Greg

Issue&Volume: 2023-11-08

Abstract: Trimethylation of histone H3 lysine 9 (H3K9me3) is crucial for the regulation of gene repression and heterochromatin formation, cell-fate determination and organismal development1. H3K9me3 also provides an essential mechanism for silencing transposable elements1–4. However, previous studies have shown that canonical H3K9me3 readers (for example, HP1 (refs. 5–9) and MPP8 (refs. 10–12)) have limited roles in silencing endogenous retroviruses (ERVs), one of the main transposable element classes in the mammalian genome13. Here we report that trinucleotide-repeat-containing 18 (TNRC18), a poorly understood chromatin regulator, recognizes H3K9me3 to mediate the silencing of ERV class I (ERV1) elements such as LTR12 (ref. 14). Biochemical, biophysical and structural studies identified the carboxy-terminal bromo-adjacent homology (BAH) domain of TNRC18 (TNRC18(BAH)) as an H3K9me3-specific reader. Moreover, the amino-terminal segment of TNRC18 is a platform for the direct recruitment of co-repressors such as HDAC–Sin3–NCoR complexes, thus enforcing optimal repression of the H3K9me3-demarcated ERVs. Point mutagenesis that disrupts the TNRC18(BAH)-mediated H3K9me3 engagement caused neonatal death in mice and, in multiple mammalian cell models, led to derepressed expression of ERVs, which affected the landscape of cis-regulatory elements and, therefore, gene-expression programmes. Collectively, we describe a new H3K9me3-sensing and regulatory pathway that operates to epigenetically silence evolutionarily young ERVs and exert substantial effects on host genome integrity, transcriptomic regulation, immunity and development. Trinucleotide-repeat-containing 18 (TNRC18), which has poorly understood functions, is now identified as an H3K9me3-specific reader that silences endogenous retroviruses.

DOI: 10.1038/s41586-023-06688-z

Source: https://www.nature.com/articles/s41586-023-06688-z

Nature：《自然》，创刊于1869年。隶属于施普林格·自然出版集团，最新IF：69.504
官方网址：http://www.nature.com/
投稿链接：http://www.nature.com/authors/submit_manuscript.html