Abstract
The distinct morphological and functional properties of the cardiac chambers arise from an elaborate developmental program involving cell lineage determination, morphogenesis, and dynamic spatiotemporal gene expression patterns. Although 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 the MEF2C transcription factor in the regulation of chamber-restricted enhancers. To better understand the mechanisms of MEF2-mediated regional gene regulation in the heart, we took advantage of MEF2A knock-out (KO) mice, a model that displays a predominantly ventricular chamber phenotype. Transcriptomic analysis of atrial and ventricular tissue from adult MEF2A KO hearts revealed a striking difference in chamber gene expression, with a larger proportion of dysregulated genes in the atrial chambers. Canonical pathway analysis of genes preferentially dysregulated in the atria and ventricles revealed distinct MEF2A-dependent cellular processes in each cardiac chamber. In the atria, MEF2A regulated genes involved in fibrosis and adhesion, whereas in the ventricles, it controlled inflammation and endocytosis. Finally, analysis of transcription factor-binding site motifs of differentially dysregulated genes uncovered distinct MEF2A co-regulators for the atrial and ventricular gene sets, and a subset of these was found to cooperate with MEF2A. In conclusion, our 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 optimal output of these gene products for proper physiological function of the atrial and ventricular chambers.
Highlights
The distinct morphological and functional properties of the cardiac chambers arise from an elaborate developmental program involving cell lineage determination, morphogenesis, and dynamic spatiotemporal gene expression patterns
To characterize potential differences in cardiac chamber gene regulation mediated by MEF2A, we dissected atrial and ventricular tissue from adult wild-type (WT) and MEF2A KO hearts, and we analyzed the extracted RNA via microarray
In this report we demonstrate that genes uniformly expressed throughout the adult heart are differentially sensitive to the loss of MEF2A
Summary
Tube [1, 2] These developmental programs lead to regional gene expression patterns that are unique to the atrial and ventricular chambers [3,4,5]. MEF2 proteins have been implicated in the regulation of atrial and ventricular chamber-restricted genes (19 –23) Based on their reported uniform expression throughout the heart, it is unlikely that MEF2 proteins alone drive chamber-specific gene programs. Adult MEF2A mutant hearts did not display ventricular dilation but showed compensatory activation of a MEF2-dependent reporter that was largely restricted to the ventricles. Our results demonstrate that MEF2A is required for proper atrial and ventricular gene expression but does not confer chamber identity These findings provide insight into the complex transcriptional mechanisms of region-specific gene expression in the mammalian heart
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