TRANSCRIPTION FACTOR GATA-4 REGULATES CARDIAC MUSCLE-SPECIFIC EXPRESSION OF THE ALPHA-MYOSIN HEAVY-CHAIN GENE
TRANSCRIPTION FACTOR GATA-4 REGULATES CARDIAC MUSCLE-SPECIFIC EXPRESSION OF THE ALPHA-MYOSIN HEAVY-CHAIN GENE
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DOI：
10.1128/mcb.14.7.4947
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发表时间：
1994-07-01
影响因子：
5.3
通讯作者：
MARKHAM, BE
中科院分区：
文献类型：
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作者：
MOLKENTIN, JD;KALVAKOLANU, DV;MARKHAM, BE
α -肌球蛋白重链（α - mhc）基因是成年啮齿动物心肌的主要结构蛋白。由于反式作用因子及其顺式作用位点的复杂相互作用，其表达仅限于心脏。然而，迄今为止，在骨骼肌细胞中也发现了调节该基因表达的因素。最近，转录因子GATA-4被确定，其组织分布仅限于心脏和内胚层来源的组织。我们最近在α - mhc基因的近端增强子中发现了两个推测的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α - mhc GATA位点相互作用以刺激心肌特异性表达。gata -4结合位点的单独或共同突变分别使成人心肌的活性降低50%和88%。来自异源启动子的GATA-4依赖性活性增强是通过α - mhc GATA位点介导的。α - mhc启动子结构与GATA-4表达载体的连接允许在骨骼肌中异位表达，但不能在成纤维细胞中表达。因此，骨骼肌中α - mhc表达的缺乏与GATA-4的缺乏相关。在三碘甲状腺原氨酸或视黄酸处理的心肌细胞中，GATA-4 DNA结合活性显著上调。假定的gata -4结合位点也存在于其他心肌表达结构基因的调控区域。这表明三碘甲状腺原氨酸和视黄酸可以通过反式调节因子协调控制心脏表型的机制。
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 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. Conjection 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.