Coordination of Engineered Factors with TET1/2 Promotes Early-Stage Epigenetic Modification during Somatic Cell Reprogramming
نویسندگان
چکیده
Somatic cell reprogramming toward induced pluripotent stem cells (iPSCs) holds great promise in future regenerative medicine. However, the reprogramming process mediated by the traditional defined factors (OSMK) 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 is up to 100-fold higher than the OSNK and the reprogramming by OySyNyK is very rapid and is initiated in 24 hr. We find that OySyNyK factors significantly increase Tet1 expression at the early stage and interact with Tet1/2 to promote reprogramming. Our studies not only establish a rapid and highly efficient iPSC reprogramming system but also uncover a mechanism by which engineered factors coordinate with TETs to regulate 5hmC-mediated epigenetic control.
منابع مشابه
O-18: Epigenetic Modification of Cloned Embryo Development; State of ART
Background: At the outset of the somatic cell nuclear transfer (SCNT) process, the chromatin structure of the somatic cell which governs its state of differentiation undergoes dramatic changes, called reprogramming, and is compelled back to the embryonic stage. However, the overall epigenetic makeup of the resultant cloned embryos has been acknowledged far different from the fertilized embryos....
متن کاملNanog, Oct4 and Tet1 interplay in establishing pluripotency
A few central transcription factors inside mouse embryonic stem (ES) cells and induced pluripotent stem (iPS) cells are believed to control the cells' pluripotency. Characterizations of pluripotent state were put forward on both transcription factor and epigenetic levels. Whereas core players have been identified, it is desirable to map out gene regulatory networks which govern the reprogrammin...
متن کاملReplacement of Oct4 by Tet1 during iPSC induction reveals an important role of DNA methylation and hydroxymethylation in reprogramming.
DNA methylation and demethylation have been proposed to play an important role in somatic cell reprogramming. Here, we demonstrate that the DNA hydroxylase Tet1 facilitates pluripotent stem cell induction by promoting Oct4 demethylation and reactivation. Moreover, Tet1 (T) can replace Oct4 and initiate somatic cell reprogramming in conjunction with Sox2 (S), Klf4 (K), and c-Myc (M). We establis...
متن کاملmiR-6539 is a novel mediator of somatic cell reprogramming that represses the translation of Dnmt3b
Global DNA hypomethylation has been shown to be involved in the pluripotency of induced pluripotent stem (iPS) cells. Relatedly, DNA methyltransferases (DNMTs) are believed to be a substantial barrier to genome-wide demethylation. There are two distinct stages of DNMT expression during iPS cell generation. In the earlier stage of reprogramming, the expression of DNMTs is repressed to overcome e...
متن کاملI-8: Somatic Cell Nuclear Reprogramming byMouse Oocytes Endures Beyond ReproductiveDecline
Background: The mammalian oocyte has the unique feature of supporting fertilization and normal development while being able of reprogramming the nuclei of somatic cells towards pluripotency, and occasionally even totipotency. Whilst oocyte quality is known to decay with somatic ageing, it is not a given that different biological functions decay concurrently. In this study, we tested whether ooc...
متن کامل