Fine-tuning Mybl2 is required for proper mesenchymal-to-epithelial transition during somatic reprogramming

During somatic reprogramming, Yamanaka’s pioneer factors regulate a complex sequence of molecular events leading to the activation of a network of pluripotency factors, ultimately resulting in the acquisition and maintenance of a pluripotent state. Here we show that, contrary to the pluripotency factors studied so far, overexpression of Mybl2, inhibits somatic reprogramming. Our results demonstrate that Mybl2 levels are crucial for the dynamics of the reprogramming process. Mybl2 overexpression changes chromatin conformation, affecting the accessibility of pioneer factors to the chromatin and promoting accessibility for early immediate response genes known to be reprogramming blockers. These changes in chromatin landscape ultimately lead to a de-regulation of key genes important for the mesenchymal-to-epithelial transition. This work defines Mybl2 level as a gatekeeper for the initiation of reprogramming, providing further insights into the tight regulation and required coordination of molecular events necessary for changes in cell fate identity during the reprogramming process.