靶向着丝粒非连续基序进行异染色质起始。

Targeting pericentric non-consecutive motifs for heterochromatin initiation.

机构信息

National Laboratory of Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing, China.

Key Laboratory of Epigenetic Regulation and Intervention, Chinese Academy of Sciences, Beijing, China.

出版信息

Nature. 2024 Jul;631(8021):678-685. doi: 10.1038/s41586-024-07640-5. Epub 2024 Jul 3.

Abstract

Pericentric heterochromatin is a critical component of chromosomes marked by histone H3 K9 (H3K9) methylation. However, what recruits H3K9-specific histone methyltransferases to pericentric regions in vertebrates remains unclear, as does why pericentric regions in different species share the same H3K9 methylation mark despite lacking highly conserved DNA sequences. Here we show that zinc-finger proteins ZNF512 and ZNF512B specifically localize at pericentric regions through direct DNA binding. Notably, both ZNF512 and ZNF512B are sufficient to initiate de novo heterochromatin formation at ectopically targeted repetitive regions and pericentric regions, as they directly recruit SUV39H1 and SUV39H2 (SUV39H) to catalyse H3K9 methylation. SUV39H2 makes a greater contribution to H3K9 trimethylation, whereas SUV39H1 seems to contribute more to silencing, probably owing to its preferential association with HP1 proteins. ZNF512 and ZNF512B from different species can specifically target pericentric regions of other vertebrates, because the atypical long linker residues between the zinc-fingers of ZNF512 and ZNF512B offer flexibility in recognition of non-consecutively organized three-nucleotide triplets targeted by each zinc-finger. This study addresses two long-standing questions: how constitutive heterochromatin is initiated and how seemingly variable pericentric sequences are targeted by the same set of conserved machinery in vertebrates.

摘要

着丝粒异染色质是由组蛋白 H3 K9(H3K9)甲基化标记的染色体的关键组成部分。然而,在脊椎动物中,是什么招募了 H3K9 特异性组蛋白甲基转移酶到着丝粒区域,以及为什么不同物种的着丝粒区域尽管缺乏高度保守的 DNA 序列,但却具有相同的 H3K9 甲基化标记,这些问题仍不清楚。在这里,我们显示锌指蛋白 ZNF512 和 ZNF512B 通过直接 DNA 结合特异性定位于着丝粒区域。值得注意的是,ZNF512 和 ZNF512B 都足以在异位靶向的重复区域和着丝粒区域启动从头异染色质形成,因为它们直接招募 SUV39H1 和 SUV39H2(SUV39H)来催化 H3K9 甲基化。SUV39H2 对 H3K9 三甲基化的贡献更大,而 SUV39H1 似乎对沉默的贡献更大,这可能是由于其与 HP1 蛋白的优先结合。来自不同物种的 ZNF512 和 ZNF512B 可以特异性靶向其他脊椎动物的着丝粒区域,因为 ZNF512 和 ZNF512B 的锌指之间的非典型长连接子残基在识别每个锌指靶向的非连续组织的三核苷酸三联体方面提供了灵活性。这项研究解决了两个长期存在的问题:如何启动组成型异染色质以及如何通过同一组保守机制靶向看似可变的着丝粒序列。

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