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.
Highlights
Reprogramming somatic cells to a pluripotent state can be achieved through transient ectopic expression of pluripotency transcription factors (Yamanaka factors), Oct[4], Sox[2], Klf[4], and c-Myc (OSKM)[1,2,3]
Tfap2c is upregulated during the induction of induced pluripotent stem cells (iPSCs) To investigate the roles of Tfap2c in regulating reprogramming, we first examined Tfap2c expression levels in mouse embryonic fibroblasts (MEFs), mouse embryonic stem cells (ESCs), and iPSCs by reanalyzing a published GEO DataSets (Accession: GSE66613)
By using MEFs derived from transgenic mice carrying Oct4-GFP/Rosa[26] (OG2-MEF), we could isolate SSEA1 positive (SSEA1+) and Oct4-GFPpositive (Oct4-GFP+) populations, which are known intermediates poised to reprogram[19,23]
Summary
Reprogramming somatic cells to a pluripotent state can be achieved through transient ectopic expression of pluripotency transcription factors (Yamanaka factors), Oct[4], Sox[2], Klf[4], and c-Myc (OSKM)[1,2,3]. Wang et al Cell Death and Disease (2020)11:482 roles in the regulation of proliferation, cell-cycle control, apoptosis, embryonic development as well as carcinogenesis[11,12]. The roles of Tfap2c in regulating somatic cell reprogramming and human naïve pluripotency were not reported until recently[19,20,21]. Transcriptional analysis of poised iPSC intermediates uncovers Tfap2c is important for the acquisition of pluripotency[19]. Any additional mechanisms accounting for the roles of Tfap2c in regulating somatic cell reprogramming are not well understood
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