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Epigenetic safeguards are coordinately removed to reverse cell identity [5hmC Enrichment]

ABSTRACT: Epigenetic modifications operate in concert to maintain cell identity, yet how these interconnected networks suppress alternative cell fates remains unknown. Here we uncover a link between the removal of repressive histone H3K9 methylation and DNA methylation during the reprogramming of somatic cells to pluripotency. The H3K9me2 demethylase, Kdm3b, transcriptionally controls DNA demethylase Tet1 expression. Unexpectedly, in the absence of Kdm3b, loci that have to be DNA demethylated are trapped in an intermediate hydroxymethylated (5hmC) state and do not resolve to unmethylated cytosine. Ectopic 5hmC trapping precludes the chromatin association of master pluripotency factor, POU5F1, and pluripotent gene activation. Tet1 but not Tet2 is critical for this defining event in the reprogramming process. Taken together we uncover a mechanism of coordinated chromatin modification removal in disrupting cell identity.

ORGANISM(S): Mus musculus

PROVIDER: GSE119076 | GEO | 2019/09/26

REPOSITORIES: GEO

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Project description:Ten-eleven translocation (TET) family enzymes can convert 5-methylcytosine (5mC) into 5-hydroxymethylcytosine (5hmC) in DNA and have been proposed as potential DNA demethylase candidates1. Evidences from recent studies indicated that Tet1 is predominantly expressed in ES cells and plays dual functions in promoting transcription of pluripotency genes and as well as participating in the repression of developmental genes by facilitating recruitment of PRC21-5. These studies further raised the possibility that Tet1 might play a role in somatic cell reprogramming. Here, we provide evidence showing that Tet1 can substitute for pluripotent transcription factors in reprogramming differentiated somatic cells to pluripotent stem cells. Tet1 can replace any one of the four traditional transcription factors including Oct4, Sox2, Klf4 and c-Myc during somatic cell reprogramming. Subsequently, the chimeric mice with germline transmission capacity could be efficiently produced from all induced pluripotent stem (iPS) cell lines reprogrammed by OT (Oct4, Tet1), TSKM (Tet1, Sox2, Klf4, c-Myc), OTK, OTKM and OSTM combinations. Furthermore, the TSKM-reprogrammed iPS cells without using Oct4 could produce viable full-term iPS mice with normal fertility through tetraploid complementation and secondary iPS cells could be induced subsequently from the somatic cells retrieved from the iPS mice. Moreover, we demonstrated that conversion of 5mC into 5hmC in Nanog promoter occurred during reprogramming, which might account in part for the mechanism of Tet1 mediated reprogramming. To our knowledge, our study provides the first evidence demonstrating that DNA modifying enzyme Tet1 can replace the pluripotent transcription factors to reprogram differentiated somatic cells to iPS cells. Gene expression profile of iPS cells and ES cells were generated by Affymetrix Mouse Gene 1.0 ST Array. The Gene expression profile of ES cell R1 was used as control. Three biological repeats were included for each line.

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Epigenetic safeguards are coordinately removed to reverse cell identity [5hmC Enrichment]

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