Two functional modes of a nuclear receptor-recruited arginine methyltransferase in transcriptional activation
Two functional modes of a nuclear receptor-recruited arginine methyltransferase in transcriptional activation
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DOI：
10.1016/j.molcel.2006.09.020
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发表时间：
2006-10-20
期刊：
影响因子：
16
通讯作者：
Malik, Sohail
中科院分区：
文献类型：
--
作者：
Barrero, Maria J.;Malik, Sohail
核受体和其他转录激活剂一样，通过招募一个复杂的协调蛋白网络来启动基因转录。在这里，我们已经确定精氨酸甲基转移酶PRMT1是HNF4的辅助激活因子，HNF4是一种孤儿核受体，调节参与多种代谢途径的基因的表达。值得注意的是，PRMT1在组蛋白H4上的甲基化活性与诱导HNF4靶基因分化肠细胞密切相关，它通过两部分机制调节HNF4的活性。首先，PRMT1与HNF4 DNA结合域(DBD)结合并甲基化，从而增强HNF4与其结合部位的亲和力。其次，PRMT1被招募到HNF4配体结合域(LBD)，这一机制涉及p160家族的辅活化子和组蛋白H4在精氨酸3处的甲基化。这与组蛋白乙酰转移酶p300的招募一起，导致核小体改变和随后的RNA聚合酶II预起始复合体的形成。
Nuclear receptors, like other transcriptional activators, switch on gene transcription by recruiting a complex network of coregulatory proteins. Here, we have identified the arginine methyltransferase PRMT1 as a coactivator for HNF4, an orphan nuclear receptor that regulates the expression of genes involved in diverse metabolic pathways. Remarkably, PRMT1, whose methylation activity on histone H4 strongly correlates with induction of HNF4 target genes in differentiating enterocytes, regulates HNF4 activity through a bipartite mechanism. First, PRMT1 binds and methylates the HNF4 DNA-binding domain (DBD), thereby enhancing the affinity of HNF4 for its binding site. Second, PRMT1 is recruited to the HNF4 ligand-binding domain (LBD) through a mechanism that involves the p160 family of coactivators and methylates histone H4 at arginine 3. This, together with recruitment of the histone acetyltransferase p300, leads to nucleosomal alterations and subsequent RNA polymerase II preinitiation complex formation.