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组蛋白修饰读取器 ZCWPW1 将组蛋白甲基化与 PRDM9 诱导的双链断裂修复联系起来。

The histone modification reader ZCWPW1 links histone methylation to PRDM9-induced double-strand break repair.

机构信息

Center for Reproductive Medicine, Cheeloo College of Medicine, Shandong University, Jinan, China.

National Research Center for Assisted Reproductive Technology and Reproductive Genetics, Shandong University, Jinan, China.

出版信息

Elife. 2020 May 6;9:e53459. doi: 10.7554/eLife.53459.

DOI:10.7554/eLife.53459
PMID:32374261
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC7314539/
Abstract

The histone modification writer Prdm9 has been shown to deposit H3K4me3 and H3K36me3 at future double-strand break (DSB) sites during the very early stages of meiosis, but the reader of these marks remains unclear. Here, we demonstrate that Zcwpw1 is an H3K4me3 reader that is required for DSB repair and synapsis in mouse testes. We generated H3K4me3 reader-dead Zcwpw1 mutant mice and found that their spermatocytes were arrested at the pachytene-like stage, which phenocopies the knock-out mice. Based on various ChIP-seq and immunofluorescence analyses using several mutants, we found that Zcwpw1's occupancy on chromatin is strongly promoted by the histone-modification activity of PRDM9. Zcwpw1 localizes to DMC1-labelled hotspots in a largely Prdm9-dependent manner, where it facilitates completion of synapsis by mediating the DSB repair process. In sum, our study demonstrates the function of ZCWPW1 that acts as part of the selection system for epigenetics-based recombination hotspots in mammals.

摘要

组蛋白修饰写入器 Prdm9 已被证明在减数分裂的早期阶段在未来的双链断裂 (DSB) 位点沉积 H3K4me3 和 H3K36me3，但这些标记的读取器仍不清楚。在这里，我们证明 Zcwpw1 是一种 H3K4me3 读取器，它是小鼠睾丸中 DSB 修复和联会所必需的。我们生成了 H3K4me3 读取器缺失的 Zcwpw1 突变小鼠，并发现它们的精母细胞停滞在类似于粗线期的阶段，这与 敲除小鼠的表型相似。基于使用几种突变体的各种 ChIP-seq 和免疫荧光分析，我们发现 Zcwpw1 在染色质上的占据被 PRDM9 的组蛋白修饰活性强烈促进。Zcwpw1 以很大程度上依赖 Prdm9 的方式定位于 DMC1 标记的热点，在那里它通过介导 DSB 修复过程促进联会的完成。总之，我们的研究表明 ZCWPW1 作为哺乳动物基于表观遗传的重组热点选择系统的一部分发挥作用。

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