During embryonic development, multipotent cardiovascular progenitor cells are specified from early mesoderm. Using mouse ESCs in which gene expression can be temporally regulated, we have found that transient expression of Mesp1 dramatically accelerates and enhances multipotent cardiovascular progenitor specification through an intrinsic and cell autonomous mechanism. Genome-wide transcriptional analysis indicates that Mesp1 rapidly activates and represses a discrete set of genes, and chromatin immunoprecipitation shows that Mesp1 directly binds to regulatory DNA sequences located in the promoter of many key genes in the core cardiac transcriptional machinery, resulting in their rapid upregulation. Mesp1 also directly represses the expression of key genes regulating other early mesoderm and endoderm cell fates. Our results demonstrate that Mesp1 acts as a key regulatory switch during cardiovascular specification, residing at the top of the hierarchy of the gene network responsible for cardiovascular cell-fate determination.
Bibliographical noteFunding Information:
We thank our colleagues who provided us with reagents and whose gifts are cited in the text. We thank members of Blanpain and Vanderhaeghen labs as well as A. de Kerchove for their constructive comments during the realization of this study. We thank P. Vanderhaeghen and William Lowry for their critical comments on the manuscript. We thank A. Viale (MSKCC Genomic Core Facility) for microarray analysis. C. Blanpain and A. Bondue are, respectively, chercheur qualifie and research fellow of the FRS/FNRS. This work was supported by a mandat d'impulsion scientifique of the FNRS, a career development award of the Human Frontier Science Program Organization (HFSPO), and by a research grant of the Schlumberger Foundation (FSER).