GATA-dependent recruitment of MEF2 proteins to target promoters
GATA-dependent recruitment of MEF2 proteins to target promoters
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DOI：
10.1093/emboj/19.9.2046
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发表时间：
2000-05-02
期刊：
影响因子：
11.4
通讯作者：
Nemer, M
中科院分区：
文献类型：
--
作者：
Morin, S;Charron, F;Nemer, M
肌细胞增强因子 2 (MEF2) 蛋白是 MADS-box 转录因子，对于所有肌肉谱系的分化至关重要，但其作用机制在很大程度上仍不清楚。在哺乳动物中，MEF2 最早表达的部位是心脏，早在胚胎第 7.5 天就可以检测到 MEF2C 同种型。MEF2C 基因失活会导致心脏发育停滞和包括心房钠尿因子 (ANF) 在内的许多心脏标志物严重下调。然而，这些启动子中的大多数不包含或包含低亲和力 MEF2 结合位点，并且它们不会被异源细胞中的任何 MEF2 蛋白显着激活，这表明 MEF2 作用依赖于富含心脏的辅助因子。我们提供的证据表明，MEF2 蛋白被细胞特异性 GATA 转录因子招募到目标启动子，并且 MEF2 增强了该组织限制性锌指蛋白家族的转录活性。功能性 MEF2/GATA-4 协同作用涉及 MEF2 DNA 结合结构域和 GATA-4 的羧基锌指之间的物理相互作用，并且需要两种蛋白的激活结构域。然而，MEF2 结合位点和 MEF2 DNA 结合能力都不是转录协同作用所必需的。这些结果揭示了 MEF2 转录调控的新途径，并为阐明 MEF2 在肌肉和非肌肉细胞中的作用机制提供了分子范式。
The myocyte enhancer factor-2 (MEF2) proteins are MADS-box transcription factors that are essential for differentiation of all muscle lineages but their mechanisms of action remain largely undefined. In mammals, the earliest site of MEF2 expression is the heart where the MEF2C isoform is detectable as early as embryonic day 7.5, Inactivation of the MEF2C gene causes cardiac developmental arrest and severe down-regulation of a number of cardiac markers including atrial natriuretic factor (ANF). However, most of these promoters contain no or low affinity MEF2 binding sites and they are not significantly activated by any MEF2 proteins in heterologous cells suggesting a dependence on a cardiac-enriched cofactor for MEF2 action. We pro,ide evidence that MEF2 proteins are recruited to target promoters by the cell-specific GATA transcription factors, and that MEF2 potentiates the transcriptional activity of this family of tissue-restricted zinc finger proteins. Functional MEF2/GATA-4 synergy involves physical interaction between the MEF2 DNA-binding domain and the carboxy zinc finger of GATA-4 and requires the activation domains of both proteins. However, neither MEF2, binding sites nor MEF2 DNA binding capacity are required for transcriptional synergy. The results unravel a novel pathway for transcriptional regulation by MEF2 and provide a molecular paradigm for elucidating the mechanisms of action of MEF2 in muscle and non-muscle cells.