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Proliferation pause as an early blockade of human cellular reprogramming toward pluripotency [Methylation analysis]

ABSTRACT: Human induced Pluripotent Stem cells (iPSCs) can be generated by enforced-expression of OCT3/4, SOX2, KLF4 and c-MYC (OSKM) via intermediate state that is labeled with a surface antigen TRA-1-60. However the event during conversion of somatic cells to TRA-1-60 positive (+) fate by OSKM is still unclear. Here we show that TRA-1-60 (+) cells emerged from ESRG (+) cells with proliferation independent manner. Overcoming the proliferation pausing phase is crucial for further progression of reprogramming. Inactivation of RB pathway is associated with the expansion of early TRA-1-60 (+) cells. Indeed, extended RB activation drastically decreased the proportion of TRA-1-60 (+) cells with marked premature senescence. An RNA-binding protein LIN41 promotes the RB inactivation and facilitates reprogramming efficiency in early stage via post-transcriptional suppression of cycline dependent kinase inhibitor p21. This LIN41/p21/RB axis was invalidated in immortalized cells which showed a resistance to oncogene-induced senescence. Thus, LIN41- mediated RB inactivation promotes to bail out of transient quiescence as a major blockade in initial phase of reprogramming.

ORGANISM(S): Homo sapiens

PROVIDER: GSE89925 | GEO | 2018/04/10

REPOSITORIES: GEO

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Proliferation pause as an early blockade of human cellular reprogramming toward pluripotency [single cell RNA-seq analysis]

Project description:Human induced Pluripotent Stem cells (iPSCs) can be generated by enforced-expression of OCT3/4, SOX2, KLF4 and c-MYC (OSKM) via intermediate state that is labeled with a surface antigen TRA-1-60. However the event during conversion of somatic cells to TRA-1-60 positive (+) fate by OSKM is still unclear. Here we show that TRA-1-60 (+) cells emerged from ESRG (+) cells with proliferation independent manner. Overcoming the proliferation pausing phase is crucial for further progression of reprogramming. Inactivation of RB pathway is associated with the expansion of early TRA-1-60 (+) cells. Indeed, extended RB activation drastically decreased the proportion of TRA-1-60 (+) cells with marked premature senescence. An RNA-binding protein LIN41 promotes the RB inactivation and facilitates reprogramming efficiency in early stage via post-transcriptional suppression of cycline dependent kinase inhibitor p21. This LIN41/p21/RB axis was invalidated in immortalized cells which showed a resistance to oncogene-induced senescence. Thus, LIN41- mediated RB inactivation promotes to bail out of transient quiescence as a major blockade in initial phase of reprogramming.

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