Class IIa Histone Deacetylases Regulate Cell Fate Transitions During Mouse Somatic Cell Reprogramming

The antagonism between classⅡa histone deacetylases (HDACs) and Myocyte Enhancer Factor 2 (MEF2) creates a signaling module that orchestrates tissue specification during embryogenesis.Here we describe the surprising role of this pathway in regulating cell fate decisions during somatic cell reprogramming by exogenous factors. MEF2 and classⅡa HDACs are low in somatic cells but rise steadily and asynchronously during reprogramming. Paradoxically, MEF2 impairs iPSC generation by preventing the requisite phase of mesenchymal-to-epithelial transition (MET), which is counteracted by classⅡa HDACs in a MEF2-binding dependent manner. Calcium/calmodulin dependent protein kinase (CaMK) exerts a dual role in this process by promoting nuclear export of classⅡa HDACs that impairs reprogramming in the initial phase but later on facilitates the acquisition of pluripotency. Therefore, the interplay between key developmental regulators defines an intricate signaling pathway that must be switched on and off to accomplish somatic cell reprogramming.