Over several years, we have two types of cis-acting elements which provide developmental and tissue specific transcriptional control over the avian skeletal and cardiac alpha-actin genes in skeletal muscle. The first is the E-box element which is closely associated pairs are required for trans-activation by some of the MyoD family members. The second is the serum response element (SRE), previously described as CBARs or CArG boxes, which as multiple copies are required for alpha-actin promoter activity. IN the case of the skeletal alpha-actin we have shown that SRF binding at three SREs can form higher-order complexes which correlate with full myogenic induction of the promoter. We determined that another nuclear factor described as F-ACT1 if present at highest levels in non-myogenic cells and replicating myoblasts, binds solely to the proximal SRE and its binding is mutually exclusive with SRF. F-F- F-ACT1 may act as a repressor the skeletal alpha-actin transcription, and cooperative promoter binding by SRF can effectively displace prebound F-ACT1. We have recently identified F-ACT1 as a C2H2 zinc finger protein of the GL-1-Kruppel family, designated YY1 which has been shown to function as a repressor or activator depending upon additional factors. This interplay between F-ACT1 and SRF might constitute on the regulated mechanisms, which modulates skeletal alpha-actin gene expression during cardiac development. This proposal examines the regulatory roles of SRF and F-ACT1 as well as their accessory proteins which modulates DNA binding activity during cardiac morphogenesis, embryoid body formation and in cardiac myocytes. We will determine the role of SRF phosphorylation in response to growth factors and the role accessory MHox factors on alpha-actin promoter activity. The SRF gene will be characterized to determine cis-acting sequences and trans-acting factors that are responsible for high level expression of SRF in the myocardium. The organization of YY1 will be examined and the accessory factory identified that regulate alpha-actin promoter activity. Finally, we will investigate the consequences of gene knockouts of srf and YY1 in ES cells and determine their role in early heart formation.
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