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Despite the success of animal cloning by somatic cell nuclear transfer ( SCNT ) in many species, the method is limited by its low efficiency. After zygotic genome activation ( ZGA ) during mouse development, a large number of endogenous retroviruses ( ERV s) are expressed, including the murine endogenous retrovirus‐L (Mu ERVL / MERVL ). In this study, we generate a series of MERVL reporter mouse strains to detect the  ZGA  event in embryos. We show that the majority of  SCNT  embryos do not undergo  ZGA , and H3K27me3 prevents  SCNT  reprogramming. Overexpression of the H3K27me3‐specific demethylase  KDM 6A, but not of  KDM 6B, improves the efficiency of  SCNT . Conversely, knockdown of  KDM 6B not only facilitates  ZGA , but also impedes ectopic Xist expression in  SCNT  reprogramming. Furthermore, knockdown of  KDM 6B increases the rate of  SCNT ‐derived embryonic stem cells from Duchenne muscular dystrophy embryos. These results not only provide insight into the mechanisms underlying failures of  SCNT , but also may extend the applications of  SCNT .

KDM 6A and KDM 6B play contrasting roles in nuclear transfer embryos revealed by MERVL reporter system