MITF interacts with the SWI/SNF subunit, BRG1, to promote GATA4 expression in cardiac hypertrophy

Abstract

The transcriptional regulation of pathological cardiac hypertrophy involves the interplay of transcription factors and chromatin remodeling enzymes. The Microphthalmia-associated transcription factor (MITF) is highly expressed in cardiomyocytes and is required for cardiac hypertrophy. However, the transcriptional mechanisms by which MITF promotes cardiac hypertrophy have not been elucidated. In this study, we tested the hypothesis that MITF promotes cardiac hypertrophy by activating transcription of pro-hypertrophy genes through interactions with the SWI/SNF chromatin remodeling complex. In an in vivo model of cardiac hypertrophy, expression of MITF and the BRG1 subunit of the SWI/SNF complex increased coordinately in response to pressure overload. Expression of MITF and BRG1 also increased in vitro when cardiomyocytes were stimulated with angiotensin II or a β-adrenergic agonist. Both MITF and BRG1 were required to increase cardiomyocyte size and activate expression of hypertrophy markers in response to β-adrenergic stimulation. We detected physical interactions between MITF and BRG1 in cardiomyocytes and found that they cooperate to regulate expression of a pro-hypertrophic transcription factor, GATA4. Our data show that MITF binds to the E box element in the GATA4 promoter and facilitates recruitment of BRG1. This is associated with enhanced expression of the GATA4 gene as evidenced by increased Histone3 lysine4 tri-methylation (H3K4me3) on the GATA4 promoter. Thus, in hypertrophic cardiomyoctes, 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.

From embryogenesis to adulthood: Critical role for GATA factors in heart development and function

“…Regulation occurs at transcriptional and post‐transcriptional levels. Downstream of these external signals, few direct activators of the Gata4 promoter have been identified with the exception of microphthalmia‐associated transcription factor, estrogen‐related receptor γ, and c‐Rel . However, we do know that these stimuli alter GATA4 activity through post‐translational modifications (PTMs) and protein–protein interactions (PPIs).…”

“…Downstream of these external signals, few direct activators of the Gata4 promoter have been identified with the exception of microphthalmiaassociated transcription factor, estrogen-related receptor γ, and c-Rel. [56][57][58] However, we do know that these stimuli alter GATA4 activity through post-translational modifications (PTMs) and protein-protein interactions (PPIs). For example, upon stimulation by erythropoietin, phenylephrine or pressure overload, the Mitogen Activated Protein Kinase (MAPK) pathways involving MEK1-ERK1/2 and p38 phosphorylate GATA4 and this modification is required for adaptive hypertrophy.…”

The histone demethylase Jarid1b mediates angiotensin II‐induced endothelial dysfunction by controlling the 3′UTR of soluble epoxide hydrolase

“…MANTIS interacts with the chromatin remodelling factor BRG1 and maintains its ATPase activity through stabilizing BRG1′s interaction with BAF155 . BRG1 protein levels were increased in AngII treated cardiomyocytes . HDACs were also involved as mediators of AngII signalling as HDAC6 null mice were resistant to skeletal muscle wasting mediated by chronic AngII signalling and inhibition of HDACs class I suppressed AngII‐mediated cardiac fibrosis and hypertrophy .…”

Udział kompleksów SWI/SNF opartych na aktywności BRG1 w determinowaniu fenotypu komórek nowotworowych

“…Obecna w C-końcowym fragmencie bromodomena umożliwia oddziaływanie enzymu z acetylowanymi i metylowanymi (H3K4me3) resztami lizyny białek histonowych, ale również z DNA. Literatura wskazuje jednak, że domena ta nie odpowiada jedynie za wiązanie kompleksu SWI/SNF z chromatyną, lecz pełni także funkcję regulatorową [5][6][7]. Aktywność enzymatyczna białka BRG1 zmienia się w toku cyklu komórkowego.…”

“…za wprowadzanie modyfikacji H3K4me3 [13,14]. Chociaż BRG1 jest powszechnie uważana za "czytnik" acetylowanych histonów, badania przeprowadzone dla genu GATA4 w kardiomiocytach linii H9c2 dowodzą, że enzym ten rozpoznaje także wspomnianą wyżej trójmetylację histonu H3, która podobnie jak acetylacja związana jest z aktywnymi transkrypcyjnie promotorami [7]. Komplex SWI/SNF można znaleźć również w obrębie genów, ponieważ jest elementem niezbędnym dla Rycina 1.…”