Assembly of methylated KDM1A and CHD1 drives androgen receptor-dependent transcription and translocation
Assembly of methylated KDM1A and CHD1 drives androgen receptor-dependent transcription and translocation
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DOI：
10.1038/nsmb.3153
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发表时间：
2016-02-01
影响因子：
16.8
通讯作者：
Schuele, Roland
中科院分区：
文献类型：
--
作者：
Metzger, Eric;Willmann, Dominica;Schuele, Roland
前列腺癌的演变是由表观遗传和遗传改变的组合驱动的，例如协调的染色体重排，称为染色体重排。在人前列腺肿瘤中发现的TMPRSS 2-ERG基因融合是染色体畸变的标志。TMPRSS 2-ERG融合与雄激素信号传导相关，并依赖于雄激素受体（AR）偶联基因转录。在这里，我们表明，二甲基化KDM 1A在K114（形成K114 me 2）的组蛋白甲基转移酶EHMT 2是一个关键事件控制雄激素依赖性基因转录和TMPRSS 2-ERG融合。我们鉴定了CHD 1作为KDM 1A K114 me 2阅读器，并通过求解共晶结构表征了KDM 1A K114 me 2-CHD 1识别模式。全基因组分析显示KDM 1A K114 me 2、CHD 1和AR在前列腺肿瘤细胞中的染色质共定位。总之，我们的数据将甲基化KDM 1A和CHD 1的组装与AR依赖性转录和基因组易位联系起来，从而为前列腺肿瘤演变过程中TMPRSS 2-ERG基因融合的形成提供了机制性见解。
Prostate cancer evolution is driven by a combination of epigenetic and genetic alterations such as coordinated chromosomal rearrangements, termed chromoplexy. TMPRSS2-ERG gene fusions found in human prostate tumors are a hallmark of chromoplexy. TMPRSS2-ERG fusions have been linked to androgen signaling and depend on androgen receptor (AR)-coupled gene transcription. Here, we show that dimethylation of KDM1A at K114 (to form K114me2) by the histone methyltransferase EHMT2 is a key event controlling androgen-dependent gene transcription and TMPRSS2-ERG fusion. We identified CHD1 as a KDM1A K114me2 reader and characterized the KDM1A K114me2-CHD1 recognition mode by solving the cocrystal structure. Genome-wide analyses revealed chromatin colocalization of KDM1A K114me2, CHD1 and AR in prostate tumor cells. Together, our data link the assembly of methylated KDM1A and CHD1 with AR-dependent transcription and genomic translocations, thereby providing mechanistic insight into the formation of TMPRSS2-ERG gene fusions during prostate-tumor evolution.