The transcription factors GATA4 and dHAND physically interact to synergistically activate cardiac gene expression through a p300-dependent mechanism
The transcription factors GATA4 and dHAND physically interact to synergistically activate cardiac gene expression through a p300-dependent mechanism
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DOI：
10.1074/jbc.m202490200
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发表时间：
2002-07-05
影响因子：
4.8
通讯作者：
Molkentin, JD
中科院分区：
文献类型：
--
作者：
Dai, YS;Cserjesi, P;Molkentin, JD
一组错综复杂的异类转录因子通过特定细胞类型特有的组合相互作用参与组织特异性基因表达的编程。锌指转录因子GATA4广泛表达于中胚层和内胚层组织，通过与其他半限制性转录因子如肌细胞增强因子2、活化T细胞核因子、血清反应因子和NKX2.5的组合作用来调节心肌细胞特异性基因的表达。在这里，我们确定GATA4也与心脏表达的基本螺旋-环-螺旋转录因子DHAND(也称为HAND2)相互作用。GATA4和DHAND协同激活心房利钠因子基因、b型利钠肽基因和a-肌球蛋白重链基因的心脏特异启动子的表达。使用人工报告构建的这种功能协同作用被证明是GATA位点依赖的，但E-box不依赖于位点。通过观察DHAND的bHLH域与GATA4的C端锌指结构域的物理相互作用，提出了转录协同作用的机制。GATA4和DHAND之间的这种转录协同作用与p300的招募有关，但与这两个因子的DNA结合活性的变化无关。此外，DHAND的bHLH域直接与p300的CH3结构域相互作用，表明GATA4、DHAND和p300之间存在更高级别的复合体。结合以前的观察，这些结果表明存在一个由p300和多个半限制性转录因子组成的增强体复合体，这些转录因子共同指定心脏中组织特异性基因的表达。
An intricate array of heterogeneous transcription factors participate in programming tissue-specific gene expression through combinatorial interactions that are unique to a given cell-type. The zinc finger-containing transcription factor GATA4, which is widely expressed in mesodermal and endodermal derived tissues, is thought to regulate cardiac myocyte-specific gene expression through combinatorial interactions with other semi-restricted transcription factors such as myocyte enhancer factor 2, nuclear factor of activated T-cells, serum response factor, and Nkx2.5. Here we determined that GATA4 also interacts with the cardiac-expressed basic helix-loop-helix transcription factor dHAND (also known as HAND2). GATA4 and dHAND synergistically activated expression of cardiac-specific promoters from the atrial natriuretic factor gene, the b-type natriuretic peptide gene, and the a-myosin heavy chain gene. Using artificial reporter constructs this functional synergy was shown to be GATA site-dependent, but E-box site-independent. A mechanism for the transcriptional synergy was suggested by the observation that the bHLH domain of dHAND physically interacted with the C-terminal zinc finger domain of GATA4 forming a higher order complex. This transcriptional synergy observed between GATA4 and dHAND was associated with p300 recruitment, but not with alterations in DNA binding activity of either factor. Moreover, the bHLH domain of dHAND directly interacted with the CH3 domain of p300 suggesting the existence of a higher order complex between GATA4, dHAND, and p300. Taken together with previous observations, these results suggest the existence of an enhanceosome complex comprised of p300 and multiple semi-restricted transcription factors that together specify tissue-specific gene expression in the heart.