REGULATION OF MEF2 TRANSCRIPTION FACTORS IN THE HEART

对心脏发育和反应的理解至关重要

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.