Deubiquitylation of histone H2A activates transcriptional initiation via trans-histone cross-talk with H3K4 di- and trimethylation
Deubiquitylation of histone H2A activates transcriptional initiation via trans-histone cross-talk with H3K4 di- and trimethylation
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DOI：
10.1101/gad.1609708
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发表时间：
2008-01-01
影响因子：
10.5
通讯作者：
Ito, Takashi
中科院分区：
文献类型：
--
作者：
Nakagawa, Takeya;Kajitani, Takuya;Ito, Takashi
转录起始是控制mRNA合成的关键步骤，并且与染色质结构和组蛋白修饰密切相关。在这里，我们表明，泛素化的H2A（ubH2A）与沉默的染色质和调节转录起始。ubH2A的水平在肝细胞再生过程中变化，并且基于再生肝脏的微阵列表达数据，我们鉴定了USP 21，一种催化ubH2A水解的泛素特异性蛋白酶。当染色质在体外组装时，ubH2A而不是H2A特异性地抑制H3K4的二甲基化和三甲基化。USP 21缓解了这种ubH2A特异性抑制。此外，体外转录分析表明，ubH2A抑制转录起始，但不是转录延伸，通过抑制H3K4甲基化。值得注意的是，ubH2A介导的抑制没有观察到H3赖氨酸4时，改变为精氨酸。此外，USP21在肝脏中的过表达上调了在肝细胞再生期间通常下调的基因。我们的研究揭示了一种新的跨组蛋白串扰模式，其中H2A泛素化控制H3K4的二甲基化和三甲基化，从而调节转录起始。
Transcriptional initiation is a key step in the control of mRNA synthesis and is intimately related to chromatin structure and histone modification. Here, we show that the ubiquitylation of H2A (ubH2A) correlates with silent chromatin and regulates transcriptional initiation. The levels of ubH2A vary during hepatocyte regeneration, and based on microarray expression data from regenerating liver, we identified USP21, a ubiquitin-specific protease that catalyzes the hydrolysis of ubH2A. When chromatin is assembled in vitro, ubH2A, but not H2A, specifically represses the di- and trimethylation of H3K4. USP21 relieves this ubH2A-specific repression. In addition, in vitro transcription analysis revealed that ubH2A represses transcriptional initiation, but not transcriptional elongation, by inhibiting H3K4 methylation. Notably, ubH2A-mediated repression was not observed when H3 Lys 4 was changed to arginine. Furthermore, overexpression of USP21 in the liver up-regulates a gene that is normally down-regulated during hepatocyte regeneration. Our studies revealed a novel mode of trans-histone cross-talk, in which H2A ubiquitylation controls the di- and trimethylation of H3K4, resulting in regulation of transcriptional initiation.