Coordination of engineered factors with TET1/2 promotes early stage epigenetic modification during somatic cell reprogramming. Y. Li1, G. Zhu2, F. Zhu2, T. Wang1, W. Jin2, W. Mu2, W. Lin2, W. Tan2, W. Li2, Y. Feng3, S. Warren1, Q. Sun2, D. Chen2, P. Jin1, State Key Laboratory of Reproductive Biology and State Key Laboratory of Biomembrane and Membrane 1) Dept Human Gen, Emory Univ, Atlanta, GA; 2) State Key Laboratory of Reproductive Biology State Key Laboratory of Biomembrane and Membrane Biotechnology, Institute of Zoology, Chinese Academy of Sciences, 1 Beichen West Road, Chaoyang, Beijing, P.R. China 100101; 3) Dept Pharmacology, Emory Univer, Atlanta, GA.

   Somatic cell reprogramming towards induced pluripotent stem cells (iPSCs) holds great promise in future regenerative medicine, however, the reprogramming process mediated by the traditional defined factors (OSNK) is slow and extremely inefficient. Here we develop a combination of modified reprogramming factors (OySyNyK), in which the transactivation domain of the Yes-associated protein is fused to defined factors, and establish a highly efficient and rapid reprogramming system. We show that the efficiency of OySyNyK-induced iPSCs was up to 100-fold higher than the OSNK, and the reprogramming by OySyNyK is very rapid and is initiated around 24 h. Notably, we found that OySyNyK-factors significantly increased the TET1 expression at the early stage, which interact with defined factors, and co-occupy the pluripotency loci. Our studies not only establish a rapid and highly efficient iPSC reprogramming system, but also uncover a novel mechanism by which engineered factors coordinate with TETs to regulate 5hmC-mediated epigenetic control.

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