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.

Transcriptome Profiling Reveals Important Transcription Factors and Biological Processes in Skin Regeneration Mediated by Mechanical Stretch

“…TFAP2C plays a vital role in initiating surface ectoderm differentiation, and TFAP2C-initiated progenitor cells can mature into functional keratinocytes ( Li et al, 2019 ). Moreover, TFAP2C can promote epithelial gene expression by directly binding to their promoters during induced pluripotent stem cell (iPSC) generation from mouse fibroblasts ( Wang et al, 2020a ). Further studies have shown that E-cadherin (CDH1), an important downstream target of TFAP2C and a critical regulator of EMT, plays a crucial role in mechanical stretch-induced skin cell regeneration and proliferation ( Huang et al, 2021 ).…”

Panobinostat Effectively Increases Histone Acetylation and Alters Chromatin Accessibility Landscape in Canine Embryonic Fibroblasts but Does Not Enhance Cellular Reprogramming

“…TF binding motif enrichment analysis of our data revealed that upon the treatment, there was an enrichment of several TF binding motifs, which play important roles in the process of reprogramming. Some TF binding motifs that were enriched in CEF after treatment, such as TEAD4 ( 63 ), TEAD3 ( 15 ), AP1 ( 15 , 64 ), NFAT: AP1 ( 65 ), AP2 ( 66 ), CEBP ( 67 , 68 ), MEIS2 ( 69 ), and NF-κB ( 70 , 71 ) are involved in the establishment of pluripotency. Specifically, the AP-1 family has previously been reported to impede somatic cell reprogramming ( 15 ).…”

Cooperative interaction between ERα and the EMT-inducer ZEB1 reprograms breast cancer cells for metastasis

“…Our findings support the notion that the pioneer factor AP2 promotes the formation of a ZEB1-ER TF comple . Al ho gh AP2 main ain the mammary epithelial state in ER + breast cancers 68,69 , it can stimulate both EMT and MET by inducing open chromatin states [70][71][72] . Moreover, we discovered that ZEB1 significantly enhances the ER recr i men o the AP2 gene TFAP2C, re l ing in he preg la ion of AP2 .…”