REGULATION OF MEF2 TRANSCRIPTION FACTORS IN THE HEART

是了解心脏发育和反应的核心 心肌对疾病的作用，是对分子的阐明 心脏基因调控的机制。这一基本领域 心脏生物学尤其难以深入研究。而当 识别顺式启动子和增强子的数据越来越多。 心脏特异转录、交易的重要元件 事实证明，针对这类序列的因素更加难以捉摸。肌肉 增强子结合因子2(MEF2)位点就是这样一种顺式调控序列 在许多骨骼和心脏基因调节区很重要。一群人 在MEF2转录因子中，四个相关人类基因的产物， 最近在这个实验室克隆了它们，并通过 结合到MEF2位点。它们代表着一个重要的机会 了解更多关于肌肉基因调控的一般知识，以及关于心脏的更多信息 尤其是决心。很明显，MEF2是一个关键的调节器 心脏特异转录的基因。除了MEF2 结合位点存在于许多(如果不是全部)心脏启动子和 促进剂，活性的MEF2因子在心肌细胞中被发现，而且， 他们的出现恰好与 表明分化的心脏表型的收缩蛋白。 这项提议的长期目标是利用MEF2作为一种手段 了解心脏测定的早期发育机制。目标1 旨在解决一些悬而未决的问题 与MEF2相关的生物学因素，特别是是否重要 它们之间可以辨别出功能上的区别。《目标2》寻求 确定MEF2因素所在的发展计划 在哺乳动物胚胎中表达。除了参加一项 骨骼肌成肌决定基因的层次结构，MEF2 几乎肯定是在心脏的早期阶段表达的；因此 它与心脏其他早期标志物的时间关系 表型是至关重要的。目标3旨在确定 MEF2表达的心脏特异性调控机制 活动。这些包括可能与其他转录的相互作用 心脏中的因素以及对MEF2的转录调控 基因本身，导致识别出更近端的 心脏细胞谱系的决定因素。

Central to the understanding of cardiac development, and of the response of the myocardium to disease, is the elucidation of the molecule mechanisms for cardiac gene regulation. This fundamental domain of cardiac biology has been particularly difficult to penetrate. While there is a growing body of data identifying cis promoter and enhancer elements important for cardiac-specific transcription, transacting factors that target such sequences have proved more elusive. The muscle enhancer-binding factor 2 (MEF2) site is one such cis regulatory sequence important in many skeletal and cardiac gene regulatory regions. A group of MEF2 transcription factors, the product of four related human genes, were recently clone in this laboratory and shown act specifically via binding to the MEF2 site. They represent an important opportunity to learn more about muscle gene regulation in general, and about cardiac determination in particular. It is clear that MEF2 is a key regulator of cardiac-specific transcription. In addition to the fact that the MEF2 binding site is present in many, if not all cardiac promoter and enhancers, active MEF2 factors are found in cardiocytes and, moreover, their presence the coincides with and perhaps precedes that of the contractile proteins indicative of the differentiated cardiac phenotype. The long-term objective of this proposal is to use MEF2 as a means to access early developmental mechanisms for cardiac determination. Aim 1 is directed at resolving certain outstanding questions about the basic biology of the MEF2 related factors, particularly whether important functional distinctions can be discerned among them. Aim 2 seeks to determine the developmental programs under which the MEF2 factors are expressed in the mammalian embryo. In addition to participating in a hierarchy with the myogenic determination genes in skeletal muscle, MEF2 is almost certainly expressed in the earliest stages of the heart; thus it temporal relationship with other early markers of the cardiac phenotype is of critical importance. Aim 3 is directed at identifying cardiac-specific regulatory mechanisms for the expression of MEF2 activity. These include possible interactions with other transcription factors in the heart, as well as the transcriptional controls on the MEF2 genes themselves, leading to the identification of more proximal determinants of the cardiac cell lineage.