The Iws1:Spt6:CTD complex controls cotranscriptional mRNA biosynthesis and HYPB/Setd2-mediated histone H3K36 methylation
The Iws1:Spt6:CTD complex controls cotranscriptional mRNA biosynthesis and HYPB/Setd2-mediated histone H3K36 methylation
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DOI：
10.1101/gad.1720008
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发表时间：
2008-12-15
影响因子：
10.5
通讯作者：
Jones, Katherine A.
中科院分区：
文献类型：
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作者：
Yoh, Sunnie M.;Lucas, Joseph S.;Jones, Katherine A.
基因表达和mRNA生物合成的许多步骤都与转录延伸相关联，并通过RNA聚合酶II （RNAPII）大亚基的c端结构域（CTD）进行组织。我们最近发现，转录延伸因子Spt6和组蛋白H3伴侣结合到Ser2P CTD上，招募Iws1和REF1/Aly mRNA输出接头，促进mRNA输出。在这里，我们发现Iws1也将HYPB/Setd2组蛋白甲基转移酶募集到RNAPII延伸复合体，并且是体内横跨c-Myc、HIV-1和PABPC1基因转录区域的H3K36三甲基化（H3K36me3）所必需的。有趣的是，Iws1或HYPB/Setd2的敲低也会增强PABPC1基因5'端的H3K27me3，而Iws1的敲低（而不是HYPB/Setd2）会增加体内HIV-1和PABPC1基因编码区域的组蛋白乙酰化。像Iws1一样，敲低HYPB/Setd2诱导大量HeLa poly(A)(+) mrna在细胞核中积累。在体外，重组Spt6选择性地结合位于CTD n端一半的不间断共识重复序列，并招募Iws1。因此，Iws1将两个不同的ctd结合蛋白Spt6和HYPB/Setd2连接在一个影响mRNA输出和活性基因组蛋白修饰状态的大复合体中。
Many steps in gene expression and mRNA biosynthesis are coupled to transcription elongation and organized through the C-terminal domain (CTD) of the large subunit of RNA polymerase II (RNAPII). We showed recently that Spt6, a transcription elongation factor and histone H3 chaperone, binds to the Ser2P CTD and recruits Iws1 and the REF1/Aly mRNA export adaptor to facilitate mRNA export. Here we show that Iws1 also recruits the HYPB/Setd2 histone methyltransferase to the RNAPII elongation complex and is required for H3K36 trimethylation (H3K36me3) across the transcribed region of the c-Myc, HIV-1, and PABPC1 genes in vivo. Interestingly, knockdown of either Iws1 or HYPB/Setd2 also enhanced H3K27me3 at the 5' end of the PABPC1 gene, and depletion of Iws1, but not HYPB/Setd2, increased histone acetylation across the coding regions at the HIV-1 and PABPC1 genes in vivo. Knockdown of HYPB/Setd2, like Iws1, induced bulk HeLa poly(A)(+) mRNAs to accumulate in the nucleus. In vitro, recombinant Spt6 binds selectively to a stretch of uninterrupted consensus repeats located in the N-terminal half of the CTD and recruits Iws1. Thus Iws1 connects two distinct CTD-binding proteins, Spt6 and HYPB/Setd2, in a megacomplex that affects mRNA export as well as the histone modification state of active genes.