Role of remodeling and spacing factor 1 in histone H2A ubiquitination-mediated gene silencing
Role of remodeling and spacing factor 1 in histone H2A ubiquitination-mediated gene silencing
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重塑和间隔因子 1 在组蛋白 H2A 泛素化介导的基因沉默中的作用
DOI：
10.1073/pnas.1711158114
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发表时间：
2017-09-19
影响因子：
11.1
通讯作者：
Wang，Hengbin
中科院分区：
文献类型：
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作者：
Zhang，Zhuo;Jones，Amanda E.;Wang，Hengbin
组蛋白H2 AK 119泛素化（H2 Aub）是由多梳抑制复合物1（PRC 1）介导的一种普遍存在的修饰，与基因沉默有关。我们报告，重塑和间隔因子1（RSF 1），RSF复合物的一个亚基，是一个H2 Aub结合蛋白。它通过以前未表征的泛素化H2 A结合（UAB）结构域读取H2 Aub。我们表明，RSF 1是所需的H2 Aub靶基因沉默和维持稳定的核小体模式在启动子区域。RSF 1在H2 Aub功能中的作用进一步得到以下观察结果的支持：RSF 1和Ring 1（非洲爪蟾PRC 1亚基介导H2 Aub）在非洲爪蟾胚胎发生过程中协调调节中胚层细胞特化和原肠胚形成。本研究表明RSF 1介导了H2 Aub的基因沉默功能。翻译后组蛋白修饰在调节基于染色质的核过程中发挥重要作用。组蛋白H2 AK 119泛素化（H2 Aub）是一种普遍存在的修饰，主要与基因沉默有关。然而，基本机制在很大程度上仍不清楚。在这里，我们报告的鉴定RSF 1（重塑和间隔因子1），一个亚基的RSF复合物，作为H2 Aub结合蛋白，介导的基因沉默功能的组蛋白修饰。RSF 1与H2 Aub特异性结合，但不与H2 Bub核小体结合，通过以前未表征的和强制性的区域，称为泛素化的H2 A结合结构域。在人类和小鼠细胞中，RSF 1调控的基因与RNF 2/Ring 1B控制的基因显著重叠，RNF 2/Ring 1B是Polycomb抑制复合物1（PRC 1）的亚基，催化H2 AK 119的泛素化。大约82%的H2 Aub富集基因，包括经典的PRC 1靶Hox基因，在其转录起始位点周围被RSF 1结合。通过Ring 1B敲除耗尽H2 Aub水平导致RSF 1结合显著降低。相比之下，RSF 1敲除不影响RNF 2/Ring 1B或H2 Aub水平，但导致H2 Aub靶基因的去阻遏，伴随着H2 Aub染色质组织的变化和连接体组蛋白H1的释放。RSF 1在H2 Aub介导的基因沉默中的作用通过基于染色质的体外转录进一步证明。最后，RSF 1和Ring 1合作调节非洲爪蟾早期胚胎发育过程中的中胚层细胞特化和原肠胚形成。综上所述，这些数据确定RSF 1作为H2 Aub阅读器，其通过在启动子区域维持稳定的核小体模式而有助于H2 Aub介导的基因沉默。
Significance Histone H2AK119 ubiquitination (H2Aub), as mediated by Polycomb repressive complex 1 (PRC1), is a prevalent modification which has been linked to gene silencing. We report that remodeling and spacing factor 1 (RSF1), a subunit of the RSF complex, is a H2Aub-binding protein. It reads H2Aub through a previously uncharacterized ubiquitinated H2A binding (UAB) domain. We show that RSF1 is required both for H2Aub-target gene silencing and for maintaining stable nucleosome patterns at promoter regions. The role of RSF1 in H2Aub function is further supported by the observation that RSF1 and Ring1, a Xenopus PRC1 subunit mediating H2Aub, regulate in concert mesodermal cell specification and gastrulation during Xenopus embryogenesis. This study reveals that RSF1 mediates the gene-silencing function of H2Aub. Posttranslational histone modifications play important roles in regulating chromatin-based nuclear processes. Histone H2AK119 ubiquitination (H2Aub) is a prevalent modification and has been primarily linked to gene silencing. However, the underlying mechanism remains largely obscure. Here we report the identification of RSF1 (remodeling and spacing factor 1), a subunit of the RSF complex, as a H2Aub binding protein, which mediates the gene-silencing function of this histone modification. RSF1 associates specifically with H2Aub, but not H2Bub nucleosomes, through a previously uncharacterized and obligatory region designated as ubiquitinated H2A binding domain. In human and mouse cells, genes regulated by RSF1 overlap significantly with those controlled by RNF2/Ring1B, the subunit of Polycomb repressive complex 1 (PRC1) which catalyzes the ubiquitination of H2AK119. About 82% of H2Aub-enriched genes, including the classic PRC1 target Hox genes, are bound by RSF1 around their transcription start sites. Depletion of H2Aub levels by Ring1B knockout results in a significant reduction of RSF1 binding. In contrast, RSF1 knockout does not affect RNF2/Ring1B or H2Aub levels but leads to derepression of H2Aub target genes, accompanied by changes in H2Aub chromatin organization and release of linker histone H1. The action of RSF1 in H2Aub-mediated gene silencing is further demonstrated by chromatin-based in vitro transcription. Finally, RSF1 and Ring1 act cooperatively to regulate mesodermal cell specification and gastrulation during Xenopus early embryonic development. Taken together, these data identify RSF1 as a H2Aub reader that contributes to H2Aub-mediated gene silencing by maintaining a stable nucleosome pattern at promoter regions.