Role of Transcription Factor MITF and SWI/SNF Chromatin Remodeling Enzymes Subunit BRG1 in the Regulation of Pathological Cardiac Hypertrophy

Download or read book Role of Transcription Factor MITF and SWI/SNF Chromatin Remodeling Enzymes Subunit BRG1 in the Regulation of Pathological Cardiac Hypertrophy written by Gaurav Mehta and published by . This book was released on 2015 with total page 76 pages. Available in PDF, EPUB and Kindle. Book excerpt: Cardiovascular disorders are the major cause of death in the western world with a total economic impact in billions of dollars. Heart failure represents a final common end point for various cardiovascular conditions and is responsible for high mortality rates. Cardiac hypertrophy is initiated as a cellular mechanism to protect the heart from increased hemodynamic load and ventricular wall tension. Contrary to physiological hypertrophy, pathological hypertrophy, if prolonged, is associated with increased cardiomyocyte loss and represents the most important factor responsible for heart failure. The hallmark feature of pathological hypertrophy is re-expression of the fetal gene program, which involves interplay between transcription factors and chromatin remodeling enzymes. The Microphthalmia-associated transcription factor (MITF) plays a critical role in the development of pathological cardiac hypertrophy in mice in response to isoproterenol and angiotensin II treatment. However, the transcriptional mechanisms by which MITF promotes cardiac hypertrophy have not been elucidated. Brahma-related gene 1 (BRG1), the catalytic ATPase subunit of the Switching defective/Sucrose Non-Fermenting (SWI/SNF) chromatin remodeling complex regulates cardiac hypertrophy in mice. Nonetheless, the transcriptional circuitry of BRG1 containing SWI/SNF complexes and the interaction with other proteins is not understood. In this study, we tested the hypothesis that MITF promotes pathological cardiac hypertrophy by activating transcription of pro-hypertrophy genes through interactions with the SWI/SNF chromatin remodeling complex. We utilized transverse aorta constriction (TAC) induced pressure overload as an in vivo model of pathological cardiac hypertrophy. The expression of MITF and the BRG1 subunit of the SWI/SNF complex increase coordinately in response to pressure overload. Expression of MITF and BRG1 also increased under in vitro conditions in cardiomyocytes isolated from adult mice when stimulated with angiotensin II. Rat heart-derived H9c2 cardiomyocytes showed a similar response when treated with isoproterenol, a known ß-adrenergic agonist. In H9c2 cells, both MITF and BRG1 were required to increase cardiomyocyte size and activate expression of hypertrophy markers: atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP) in response to ß-adrenergic stimulation. We detected physical interactions between the heart specific isoform of MITF (MITF-H) and BRG1 in cardiomyocytes as well as HEK 293T cells and found that they cooperate to regulate expression of a pro-hypertrophic transcription factor, GATA4. By utilizing Chromatin immunoprecipitation (ChIP), luciferase, and electrophoretic mobility shift assays, we demonstrate that MITF binds to the E box element in the GATA4 promoter. The binding of MITF facilitates recruitment of BRG1 and is associated with enhanced expression of the GATA4 gene as evidenced by increased Histone3 lysine4 tri-methylation (H3K4me3), an active mark of transcription on the GATA4 promoter. Further, down regulating MITF and BRG1 independently results in a significant abrogation in the expression of the GATA4 gene in H9c2 cells when treated with isoproterenol. Thus, in conclusion, we provide evidence that in hypertrophic cardiomyocytes, MITF is a key transcriptional activator of a pro-hypertrophic gene, GATA4, and this regulation is dependent upon the BRG1 component of the SWI/SNF complex.