Role of the serum response factor in regulating contractile apparatus gene expression and sarcomeric integrity in cardiomyocytes. J Biol Chem 2006 Mar 10;281(10):6498-510
Date
12/22/2005Pubmed ID
16368687DOI
10.1074/jbc.M509487200Scopus ID
2-s2.0-33646554187 (requires institutional sign-in at Scopus site) 84 CitationsAbstract
The serum response factor (SRF) is a transcriptional regulator required for mesodermal development, including heart formation and function. Previous studies have described the role of SRF in controlling expression of structural genes involved in conferring the myogenic phenotype. Recent studies by us and others have demonstrated embryonic lethal cardiovascular phenotypes in SRF-null animals, but have not directly addressed the mechanistic role of SRF in controlling broad regulatory programs in cardiac cells. In this study, we used a loss-of-function approach to delineate the role of SRF in cardiomyocyte gene expression and function. In SRF-null neonatal cardiomyocytes, we observed severe defects in the contractile apparatus, including Z-disc and stress fiber formation, as well as mislocalization and/or attenuation of sarcomeric proteins. Consistent with this, gene array and reverse transcription-PCR analyses showed down-regulation of genes encoding key cardiac transcriptional regulatory factors and proteins required for the maintenance of sarcomeric structure, function, and regulation. Chromatin immunoprecipitation analysis revealed that at least a subset of these proteins are likely regulated directly by SRF. The results presented here indicate that SRF is an essential coordinator of cardiomyocyte function due to its ability to regulate expression of numerous genes (some previously identified and at least 28 targets newly identified in this study) that are involved in multiple and disparate levels of sarcomeric function and assembly.
Author List
Balza RO Jr, Misra RPAuthor
Ravindra P. Misra PhD Associate Provost, Professor in the Biochemistry department at Medical College of WisconsinMESH terms used to index this publication - Major topics in bold
AnimalsAnimals, Newborn
Gene Expression Regulation
Male
Mice
Mice, Knockout
Mutation
Myocardial Contraction
Myocytes, Cardiac
Oligonucleotide Array Sequence Analysis
Reverse Transcriptase Polymerase Chain Reaction
Sarcomeres
Sequence Deletion
Serum Response Factor
