The trithorax group proteins Kismet and ASH1 promote H3K36 dimethylation to counteract Polycomb group repression in Drosophila
The trithorax group proteins Kismet and ASH1 promote H3K36 dimethylation to counteract Polycomb group repression in Drosophila
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DOI：
10.1242/dev.095786
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发表时间：
2013-10-15
期刊：
影响因子：
4.6
通讯作者：
Tamkun, John W.
中科院分区：
文献类型：
--
作者：
Dorighi, Kristel M.;Tamkun, John W.
Polycomb组的阻遏物和三胸组的激活物的成员通过修饰核小体组蛋白或重塑染色质来维持可遗传的转录状态。虽然已经取得了巨大的进展，朝着定义多梳和三胸组蛋白的生化活性，还有很多要了解它们如何相互作用，以及一般的转录机制，以维持或关闭状态的基因表达。三胸组蛋白Kismet（KIS）与染色质重塑因子的SWI/SNF和CHD家族相关。KIS促进转录延伸，促进三胸组组蛋白甲基转移酶ASH 1和TRX与活性基因的结合，并抵消Polycomb组蛋白对赖氨酸27（H3 K27）上组蛋白H3的抑制性甲基化。在这里，我们试图阐明KIS的作用机制，以及它如何与ASH 1相互作用，以拮抗果蝇中的H3 K27甲基化。我们提出的证据表明，KIS通过不同的机制促进转录延伸并抵消Polycomb组的抑制。转录延伸的化学抑制剂DRB对ASH 1募集或H3 K27甲基化没有影响。相反，ASH 1功能的丧失对转录延伸没有影响。kis中的突变导致组蛋白H3在赖氨酸36（H3 K36）修饰上的二甲基化和三甲基化的整体减少，所述赖氨酸36修饰在体外拮抗H3 K27甲基化。此外，ASH 1的缺失显著降低了H3 K36二甲基化，进一步证明ASH 1在体内是H3 K36二甲基酶。这些和其他研究结果表明，KIS拮抗Polycomb组抑制促进ASH 1依赖性H3 K36二甲基化。
Members of the Polycomb group of repressors and trithorax group of activators maintain heritable states of transcription by modifying nucleosomal histones or remodeling chromatin. Although tremendous progress has been made toward defining the biochemical activities of Polycomb and trithorax group proteins, much remains to be learned about how they interact with each other and the general transcription machinery to maintain on or off states of gene expression. The trithorax group protein Kismet (KIS) is related to the SWI/SNF and CHD families of chromatin remodeling factors. KIS promotes transcription elongation, facilitates the binding of the trithorax group histone methyltransferases ASH1 and TRX to active genes, and counteracts repressive methylation of histone H3 on lysine 27 (H3K27) by Polycomb group proteins. Here, we sought to clarify the mechanism of action of KIS and how it interacts with ASH1 to antagonize H3K27 methylation in Drosophila. We present evidence that KIS promotes transcription elongation and counteracts Polycomb group repression via distinct mechanisms. A chemical inhibitor of transcription elongation, DRB, had no effect on ASH1 recruitment or H3K27 methylation. Conversely, loss of ASH1 function had no effect on transcription elongation. Mutations in kis cause a global reduction in the di-and tri-methylation of histone H3 on lysine 36 (H3K36) - modifications that antagonize H3K27 methylation in vitro. Furthermore, loss of ASH1 significantly decreases H3K36 dimethylation, providing further evidence that ASH1 is an H3K36 dimethylase in vivo. These and other findings suggest that KIS antagonizes Polycomb group repression by facilitating ASH1-dependent H3K36 dimethylation.