Transcription factor MEF2A fine-tunes gene expression in the atrial and ventricular chambers of the adult mouse heart
Medrano, Jose Luis
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The distinct morphological and functional properties of mammalian heart chambers arise from an elaborate developmental program involving cell lineage determination, morphogenesis, and dynamic spatiotemporal gene expression patterns. While a number of transcription factors have been identified for proper gene regulation in the chambers, the complete transcriptional network that controls these patterns remains poorly defined. Previous studies have implicated MEF2 transcription factors in the regulation of chamber-restricted enhancers. To better understand the mechanisms of MEF2-mediated regional gene regulation in the heart, MEF2A knockout (KO) mice, a model that displays a predominantly ventricular chamber phenotype, are used herein. Transcriptomic analysis of atrial and ventricular tissue from adult MEF2A KO hearts revealed extensive differences in chamber gene expression across the heart, with a larger proportion of dysregulated genes in atrial chambers. Thus, it is hypothesized that MEF2A differentially regulates expression of target genes and cellular pathways in cardiac chambers. Functional pathway analysis of genes preferentially dysregulated in the atria and ventricles supported this hypothesis and revealed distinct MEF2A-dependent cellular processes in each cardiac chamber. In atria, MEF2A regulated the expression of genes involved in fibrosis and adhesion, whereas in ventricles, it controlled genes involved in inflammation and endocytosis. Additional studies uncovered preferential dysregulation of molecular components of these pathways in MEF2A KO hearts. Phosphorylated focal adhesion kinase (FAK) levels, relating to cell adhesion, were preferentially downregulated in KO atria, and TRAF6 proteins levels, relating to inflammation, were preferentially downregulated in KO ventricles. Finally, analysis of transcription factor binding site motifs of differentially dysregulated genes uncovered distinct MEF2A coregulators for the atrial and ventricular gene sets. A subset of these transcriptional coregulators were found to cooperate with MEF2A to activate MEF2-dependent reporters in vitro. In conclusion, these results suggest a mechanism in which MEF2 transcriptional activity is differentially recruited to fine-tune gene expression levels in each cardiac chamber. This regulatory mechanism ensures the optimal output of gene products for proper physiological function of the atrial and ventricular chambers. Lastly, one of the preferentially dysregulated genes, Bex1, was further characterized. Future studies will focus on the role of MEF2A-regulated Bex1 in the adult heart.