Dataset Information

TFAP2C facilitates somatic cell reprogramming by inhibiting c-Myc-dependent apoptosis and promoting mesenchymal-to-epithelial transition.

ABSTRACT: Transcription factors are known to mediate the conversion of somatic cells to induced pluripotent stem cells (iPSCs). Transcription factor TFAP2C plays important roles in the regulation of embryonic development and carcinogenesis; however, the roles of Tfap2c in regulating somatic cell reprogramming are not well understood. Here we demonstrate Tfap2c is induced during the generation of iPSCs from mouse fibroblasts and acts as a facilitator for iPSCs formation. Mechanistically, the c-Myc-dependent apoptosis, which is a roadblock to reprogramming, can be significantly mitigated by Tfap2c overexpression. Meanwhile, Tfap2c can greatly promote mesenchymal-to-epithelial transition (MET) at initiation stage of OSKM-induced reprogramming. Further analysis of gene expression and targets of Tfap2c during reprogramming by RNA-sequencing (RNA-seq) and ChIP-qPCR indicates that TFAP2C can promote epithelial gene expression by binding to their promoters directly. Finally, knockdown of E-cadherin (Cdh1), an important downstream target of TFAP2C and a critical regulator of MET antagonizes Tfap2c-mediated reprogramming. Taken together, we conclude that Tfap2c serves as a strong activator for somatic cell reprogramming through promoting the MET and inhibiting c-Myc-dependent apoptosis.

SUBMITTER: Wang Y

PROVIDER: S-EPMC7316975 | biostudies-literature | 2020 Jun

REPOSITORIES: biostudies-literature

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TFAP2C facilitates somatic cell reprogramming by inhibiting c-Myc-dependent apoptosis and promoting mesenchymal-to-epithelial transition.

Wang Yuan Y Chen Shuang S Jiang Qingyuan Q Deng Jie J Cheng Fuyi F Lin Yi Y Cheng Lin L Ye Yixin Y Chen Xiaolei X Yao Yunqi Y Zhang Xiaomei X Shi Gang G Dai Lei L Su Xiaolan X Peng Yong Y Deng Hongxin H

Cell death & disease 20200625 6

Transcription factors are known to mediate the conversion of somatic cells to induced pluripotent stem cells (iPSCs). Transcription factor TFAP2C plays important roles in the regulation of embryonic development and carcinogenesis; however, the roles of Tfap2c in regulating somatic cell reprogramming are not well understood. Here we demonstrate Tfap2c is induced during the generation of iPSCs from mouse fibroblasts and acts as a facilitator for iPSCs formation. Mechanistically, the c-Myc-dependen ...[more]

PMID: 32587258

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Project description:BackgroundIdentifying novel regulatory factors and uncovered mechanisms of somatic cell reprogramming will be helpful for basic research and clinical application of induced pluripotent stem cells (iPSCs). Sin3a, a multifunctional transcription regulator, has been proven to be involved in the maintenance of pluripotency in embryonic stem cells (ESCs), but the role of Sin3a in somatic cell reprogramming remains unclear.MethodsRNA interference of Sin3a during somatic cell reprogramming was realized by short hairpin RNAs. Reprogramming efficiency was evaluated by the number of alkaline phosphatase (AP)-positive colonies and Oct4-GFP-positive colonies. RNA sequencing was performed to identify the influenced biological processes after Sin3a knockdown and further confirmed by quantitative RT-PCR (qRT-PCR), western blotting and flow cytometry. The interaction between Sin3a and Tet1 was detected by coimmunoprecipitation. The enrichment of Sin3a and Tet1 at the epithelial gene promoters was measured by chromatin immunoprecipitation. Furthermore, DNA methylation patterns at the gene loci were investigated by hydroxymethylated DNA immunoprecipitation. Finally, Sin3a mutants that disrupt the interaction of Sin3a and Tet1 were also introduced to assess the importance of the Sin3a-Tet1 interaction during the mesenchymal-to-epithelial transition (MET) process.ResultsWe found that Sin3a was gradually increased during OSKM-induced reprogramming and that knockdown of Sin3a significantly impaired MET at the early stage of reprogramming and iPSC generation. Mechanistic studies showed that Sin3a recruited Tet1 to facilitate the hydroxymethylation of epithelial gene promoters. Moreover, disrupting the interaction of Sin3a and Tet1 significantly blocked MET and iPSC generation.ConclusionsOur studies revealed that Sin3a was a novel mediator of MET during early reprogramming, where Sin3a functioned as an epigenetic coactivator, cooperating with Tet1 to activate the epithelial program and promote the initiation of somatic cell reprogramming. These findings highlight the importance of Sin3a in the MET process and deepen our understanding of the epigenetic regulatory network of early reprogramming.

Dataset Information

TFAP2C facilitates somatic cell reprogramming by inhibiting c-Myc-dependent apoptosis and promoting mesenchymal-to-epithelial transition.

Publications

TFAP2C facilitates somatic cell reprogramming by inhibiting c-Myc-dependent apoptosis and promoting mesenchymal-to-epithelial transition.

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