Regulation of Histone H2A and H2B Deubiquitination and Xenopus Development by USP12 and USP46
Regulation of Histone H2A and H2B Deubiquitination and Xenopus Development by USP12 and USP46
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DOI：
10.1074/jbc.m110.158311
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发表时间：
2011-03-04
影响因子：
4.8
通讯作者：
Wang, Hengbin
中科院分区：
文献类型：
--
作者：
Joo, Heui-Yun;Jones, Amada;Wang, Hengbin
翻译后的组蛋白修饰在调节基因表达程序中起着重要的作用，而基因表达程序又决定了细胞的命运和发育过程中的谱系承诺。其中一种修饰是组蛋白泛素化，主要针对组蛋白H_2A和H_2B。虽然H_2A和H_2B泛素化通常分别与基因沉默和基因激活有关，但组蛋白泛素化在真核生物发育过程中的作用还不是很清楚。在这里，我们确定USP12和USP46是组蛋白H_2A和H_2B去泛素酶，它们调节非洲爪哇的发育。USP12和USP46偏好核小体底物，并在体外和体内去泛素化组蛋白H_2A和H_2B。WDR48是一种包含WD40重复的蛋白，与USP12和USP46相互作用，是组蛋白去泛素化活性所必需的。任何一个基因的过表达都会导致原肠发育缺陷，而不会影响中胚层细胞的命运，而在非洲爪哇胚胎中，USP12的敲除会导致原肠胚期中胚层基因的一个子集减少。免疫组织化学染色和染色质免疫沉淀分析表明，USP12调节组蛋白在中胚层和非洲爪哇发育过程中特定基因启动子上的去泛素化。综上所述，本研究确定USP12和USP46为组蛋白H_2A和H_2B去泛素酶，并揭示了USP12调控非洲爪哇原肠胚期的发育。
Post-translational histone modifications play important roles in regulating gene expression programs, which in turn determine cell fate and lineage commitment during development. One such modification is histone ubiquitination, which primarily targets histone H2A and H2B. Although ubiquitination of H2A and H2B has been generally linked to gene silencing and gene activation, respectively, the functions of histone ubiquitination during eukaryote development are not well understood. Here, we identified USP12 and USP46 as histone H2A and H2B deubiquitinases that regulate Xenopus development. USP12 and USP46 prefer nucleosomal substrates and deubiquitinate both histone H2A and H2B in vitro and in vivo. WDR48, a WD40 repeat-containing protein, interacts with USP12 and USP46 and is required for the histone deubiquitination activity. Overexpression of either gene leads to gastrulation defects without affecting mesodermal cell fate, whereas knockdown of USP12 in Xenopus embryos results in reduction of a subset of mesodermal genes at gastrula stages. Immunohistochemical staining and chromatin immunoprecipitation assays revealed that USP12 regulates histone deubiquitination in the mesoderm and at specific gene promoters during Xenopus development. Taken together, this study identifies USP12 and USP46 as histone deubiquitinases for H2A and H2B and reveals that USP12 regulates Xenopus development during gastrula stages.