Abstract
Proper formation of the mammalian heart requires precise spatiotemporal transcriptional regulation of gene programs in cardiomyocytes. Sophisticated regulatory networks have evolved to not only integrate the activities of distinct transcription factors to control tissue-specific gene programs but also, in many instances, to incorporate multiple members within these transcription factor families to ensure accuracy and specificity in the system. Unsurprisingly, perturbations in this elaborate transcriptional circuitry can lead to severe cardiac abnormalities. Myocyte enhancer factor–2 (MEF2) transcription factor belongs to the evolutionarily conserved cardiac gene regulatory network. Given its central role in muscle gene regulation and its evolutionary conservation, MEF2 is considered one of only a few core cardiac transcription factors. In addition to its firmly established role as a differentiation factor, MEF2 regulates wide variety of, sometimes antagonistic, cellular processes such as cell survival and death. Vertebrate genomes encode multiple MEF2 family members thereby expanding the transcriptional potential of this core transcription factor in the heart. This review highlights the requirement of the MEF2 family and their orthologs in cardiac development in diverse animal model systems. Furthermore, we describe the recently characterized role of MEF2 in direct reprogramming and genome-wide cardiomyocyte gene regulation. A thorough understanding of the regulatory functions of the MEF2 family in cardiac development and cardiogenomics is required in order to develop effective therapeutic strategies to repair the diseased heart.
Highlights
Development of the mammalian heart is a complex process that requires precise coordination of cardiomyocyte specification, proliferation, differentiation, and growth
We have learned a considerable amount about Myocyte enhancer factor–2 (MEF2) function in cardiac development through the genetic dissection of MEF2 orthologs in flies, fish, and mammals, but there is still valuable information that can be extracted regarding their function in cardiomyocytes from these and other model systems with further experimentation
With the availability of genome-wide data describing de novo mutations in human cardiovascular disease, these large data sets could be surveyed for MEF2 mutations and, with current gene editing tools such as CRISPR/Cas9, specific mutations engineered in the MEF2 genes to assess phenotypic effects in vivo
Summary
Development of the mammalian heart is a complex process that requires precise coordination of cardiomyocyte specification, proliferation, differentiation, and growth. A number of transcript variants can be generated by alternative splicing [8], presumably leading to MEF2 protein isoforms with distinct transcriptional activities Their ability to form homo- and heterodimers adds an important layer of specificity to their transcriptional regulatory function. In most instances in vitro reporter assays fail to recapitulate in vivo regulatory differences between the MEF2 family members Despite these obstacles, analysis of gain-of- and loss-of-function mutations in model systems have revealed dramatically different cardiac phenotypes and dysregulated gene expression profiles for the vertebrate MEF2 isoforms suggesting that family members harbor unique regulatory activities. A deeper appreciation of the cardiac phenotypes associated with mutations in MEF2 orthologs in diverse model systems and the gene programs regulated by this family of transcription factors will be essential for the development of therapeutic approaches to treat heart disease
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