Menin links estrogen receptor activation to histone H3K4 trimethylation
Menin links estrogen receptor activation to histone H3K4 trimethylation
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DOI：
10.1158/0008-5472.can-05-4461
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发表时间：
2006-05-01
期刊：
影响因子：
11.2
通讯作者：
Timmers, H. Th. Marc
中科院分区：
文献类型：
--
作者：
Dreijerink, Koen M. A.;Mulder, Klaas W.;Timmers, H. Th. Marc
多发性内分泌瘤1型（MEN 1）肿瘤抑制基因的产物menin是MLL 1/MLL 2组蛋白甲基转移酶复合物的组成部分，对组蛋白H3（H3 K4）的Lys 4具有特异性。我们发现，menin是雌激素和维生素D的核受体的转录共激活因子。内源性雌激素响应性TFF 1（pS2）基因的激活导致menin的启动子募集和H3 K4的三甲基化升高。menin的敲低降低了激活的TFF 1（pS2）转录和H3 K4三甲基化。此外，menin可以直接与雌激素受体-α（ER α）以雌激素依赖的方式相互作用。大多数疾病相关的MEN 1突变阻止menin-ER α。互动重要的是，ER α相互作用的突变体在共激活因子功能上也有缺陷。我们的研究结果表明，menin是一个关键的联系招募组蛋白甲基转移酶复合物和核受体介导的转录。
The product of the multiple endocrine neoplasia type 1 (MEN1) tumor suppressor gene, menin, is an integral component of MLL1/MLL2 histone methyltransferase complexes specific for Lys4 of histone H3 (H3K4). We show that menin is a transcriptional coactivator of the nuclear receptors for estrogen and vitamin D. Activation of the endogenous estrogen-responsive TFF1 (pS2) gene results in promoter recruitment of menin and in elevated trimethylation of H3K4. Knockdown of menin reduces both activated TFF1 (pS2) transcription and H3K4 trimethylation. In addition, menin can directly interact with the estrogen receptor-alpha (ER alpha) in a hormone-dependent manner. The majority of disease-related MEN1 mutations prevent menin-ER alpha. interaction. Importantly, ER alpha-interacting mutants are also defective in coactivator function. Our results indicate that menin is a critical link between recruitment of histone methyltransferase complexes and nuclear receptor-mediated transcription.