CBP-mediated acetylation of histone H3 lysine 27 antagonizes Drosophila Polycomb silencing
CBP-mediated acetylation of histone H3 lysine 27 antagonizes Drosophila Polycomb silencing
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DOI：
10.1242/dev.037127
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发表时间：
2009-09-15
期刊：
影响因子：
4.6
通讯作者：
Harte, Peter J.
中科院分区：
文献类型：
--
作者：
Tie, Feng;Banerjee, Rakhee;Harte, Peter J.
Polycomb阻遏复合物2（PRC 2）引起的组蛋白H3赖氨酸27（H3 K27 me 3）的三甲基化对于Polycomb靶基因的转录沉默是必不可少的，而H3 K27（H3 K27 ac）的乙酰化最近被证明与许多活性哺乳动物基因相关。与组蛋白乙酰转移酶CBP相关的三胸蛋白（TRX）是维持转录活性状态所必需的，并拮抗Polycomb沉默，尽管这种拮抗作用的机制尚不清楚。在这里，我们表明，H3 K27是专门乙酰化的果蝇CBP和其脱乙酰化涉及RPD 3。H3 K27 ac在早期胚胎中以高水平存在，并在4小时后随着H3 K27 me 3的增加而下降。E（Z）的敲低减少了大量组蛋白中的H3 K27 me 3并增加了H3 K27 ac，并且在受抑制的Polycomb靶基因abd-A的启动子处，这表明这些确实在一些H3 K27位点处构成了替代修饰。CBP在体内的中度过表达导致H3 K27 ac的整体增加和H3 K27 me 3的减少，并强烈增强Polycomb突变体表型。我们还表明，TRX是所需的H3 K27乙酰化。TRX过表达还引起H3 K27 ac的增加和H3 K27 me 3的伴随减少，并导致Polycomb沉默的缺陷。染色质免疫沉淀结合DNA微阵列（ChIP芯片）分析表明，H3 K27 ac和H3 K27 me 3是互斥的，H3 K27 ac和H3 K4 me 3信号在大多数位点重合。我们认为CBP对H3 K27的TRX依赖性乙酰化作用阻止了Polycomb靶基因的H3 K27 me 3，并构成了TRX拮抗或阻止Polycomb沉默的分子机制的关键部分。
Trimethylation of histone H3 lysine 27 (H3K27me3) by Polycomb repressive complex 2 (PRC2) is essential for transcriptional silencing of Polycomb target genes, whereas acetylation of H3K27 (H3K27ac) has recently been shown to be associated with many active mammalian genes. The Trithorax protein (TRX), which associates with the histone acetyltransferase CBP, is required for maintenance of transcriptionally active states and antagonizes Polycomb silencing, although the mechanism underlying this antagonism is unknown. Here we show that H3K27 is specifically acetylated by Drosophila CBP and its deacetylation involves RPD3. H3K27ac is present at high levels in early embryos and declines after 4 hours as H3K27me3 increases. Knockdown of E(Z) decreases H3K27me3 and increases H3K27ac in bulk histones and at the promoter of the repressed Polycomb target gene abd-A, suggesting that these indeed constitute alternative modifications at some H3K27 sites. Moderate overexpression of CBP in vivo causes a global increase in H3K27ac and a decrease in H3K27me3, and strongly enhances Polycomb mutant phenotypes. We also show that TRX is required for H3K27 acetylation. TRX overexpression also causes an increase in H3K27ac and a concomitant decrease in H3K27me3 and leads to defects in Polycomb silencing. Chromatin immunoprecipitation coupled with DNA microarray (ChIP-chip) analysis reveals that H3K27ac and H3K27me3 are mutually exclusive and that H3K27ac and H3K4me3 signals coincide at most sites. We propose that TRX-dependent acetylation of H3K27 by CBP prevents H3K27me3 at Polycomb target genes and constitutes a key part of the molecular mechanism by which TRX antagonizes or prevents Polycomb silencing.