Epigenetic regulation of "differentiation timing" of cardiovascular cells

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Velocity of cell differentiation is strictly controlled and is crucial for normal development and stem cell differentiation. However, underlying mechanisms regulating differentiation velocity are fully unknown. Here we show a molecular mechanism determining differentiation velocity from mouse embryonic stem cells(ESCs). Activation of protein kinase A(PKA) accelerates differentiation velocity to induce approximately 2-times earlier appearance of mesoderm and other germ layer cells, reciprocally correlated with the earlier disappearance of pluripotent markers after ESC differentiation. PKA activation increased protein expression of G9a, a H3K9 methyltransferase, along with earlier H3K9 dimethylation and DNA methylation in Oct3/4 and Nanog gene promoters. Deletion of G9a completely abolished PKA-elicited acceleration of differentiation and epigenetic modification. Furthermore, G9a knockout mice showed prolonged expressions of Oct3/4 and Nanog at embryonic day-7. 5 and delayed development.