首页> 外文期刊>Molecular and Cellular Biology >Transcription factor GATA-4 regulates cardiac muscle-specific expression of the alpha-myosin heavy-chain gene.
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Transcription factor GATA-4 regulates cardiac muscle-specific expression of the alpha-myosin heavy-chain gene.

机译:转录因子GATA-4调节α-肌球蛋白重链基因的心肌特异性表达。

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The alpha-myosin heavy-chain (alpha-MHC) gene is the major structural protein in the adult rodent myocardium. Its expression is restricted to the heart by a complex interplay of trans-acting factors and their cis-acting sites. However, to date, the factors that have been shown to regulate expression of this gene have also been found in skeletal muscle cells. Recently, transcription factor GATA-4, which has a tissue distribution limited to the heart and endodermally derived tissues, was identified. We recently found two putative GATA-binding sites within the proximal enhancer of the alpha-MHC gene, suggesting that GATA-4 might regulate its expression. In this study, we establish that GATA-4 interacts with the alpha-MHC GATA sites to stimulate cardiac muscle-specific expression. Mutation of the GATA-4-binding sites either individually or together decreased activity by 50 and 88% in the adult myocardium, respectively. GATA-4-dependent enhancement of activity from a heterologous promoter was mediated through the alpha-MHC GATA sites. Coinjection of an alpha-MHC promoter construct with a GATA-4 expression vector permitted ectopic expression in skeletal muscle but not in fibroblasts. Thus, the lack of alpha-MHC expression in skeletal muscle correlates with a lack of GATA-4. GATA-4 DNA binding activity was significantly up-regulated in triiodothyronine- or retinoic acid-treated cardiomyocytes. Putative GATA-4-binding sites are also found in the regulatory regions of other cardiac muscle-expressed structural genes. This indicates a mechanism whereby triiodothyronine and retinoic acid can exert coordinate control of the cardiac phenotype through a trans-acting regulatory factor.
机译:α-肌球蛋白重链(α-MHC)基因是成年啮齿动物心肌中的主要结构蛋白。反式作用因子及其顺式作用位点之间的复杂相互作用限制了它的表达。然而,迄今为止,在骨骼肌细胞中也发现了已显示出调节该基因表达的因子。最近,鉴定了转录因子GATA-4,其组织分布限于心脏和内胚层来源的组织。我们最近在alpha-MHC基因的近端增强子中发现了两个推定的GATA结合位点,表明GATA-4可能调节其表达。在这项研究中,我们确定GATA-4与alpha-MHC GATA位点相互作用以刺激心肌特异性表达。在成人心肌中,单独或共同改变GATA-4结合位点的活性分别降低了50%和88%。通过α-MHCGATA位点介导了来自异源启动子的GATA-4依赖性活性增强。 α-MHC启动子构建体与GATA-4表达载体的共同注射允许异位表达在骨骼肌中,但不能在成纤维细胞中。因此,骨骼肌中α-MHC表达的缺乏与GATA-4的缺乏有关。在三碘甲状腺素或视黄酸处理的心肌细胞中,GATA-4 DNA结合活性显着上调。在其他心肌表达的结构基因的调控区中也发现了假定的GATA-4结合位点。这表明三碘甲甲状腺素和视黄酸可以通过反式调节因子对心脏表型进行协调控制的机制。

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