Forkhead box family transcription factors as versatile regulators for cellular reprogramming to pluripotency

Meijun Fu,Ziyu Feng,Huan Chen,Shangtao Cao,Jing Guo,Jing Liu,Zepo Cai,Mengying Zeng,Baomei Cai,Yihang Yang,Chunhua Zhou,Pinghui Zhu,Yue Qin,Shengyong Yu,Lijun Chen,Duanqing Pei

doi:10.1186/s13619-021-00078-4

Abstract

Forkhead box (Fox) transcription factors play important roles in mammalian development and disease. However, their function in mouse somatic cell reprogramming remains unclear. Here, we report that FoxD subfamily and FoxG1 accelerate induced pluripotent stem cells (iPSCs) generation from mouse fibroblasts as early as day4 while FoxA and FoxO subfamily impede this process obviously. More importantly, FoxD3, FoxD4 and FoxG1 can replace Oct4 respectively and generate iPSCs with germline transmission together with Sox2 and Klf4. On the contrary, FoxO6 almost totally blocks reprogramming through inhibiting cell proliferation, suppressing the expression of pluripotent genes and hindering the process of mesenchymal to epithelial transition (MET). Thus, our study uncovers unexpected roles of Fox transcription factors in reprogramming and offers new insights into cell fate transition.

Highlights

Reprogramming somatic cells to induced pluripotent stem cells by defined transcription factors is a revolutionary concept for biology and medicine, providing cellular sources for disease therapy and models for investigating roles of cell fate decision (Takahashi et al, 2007; Takahashi and Yamanaka, 2006; Yamanaka, 2020)
To gain insight of any role Forkhead box (Fox) genes may play in pluripotency, we analyzed the expression of members of Fox transcription factor family in mouse embryonic fibroblast (MEF),mouse embryonic stem cells and during somatic cell reprogramming and mouse early embryo development from E3.5 to 7.5. the results revealed that they varied broadly, indicating these genes might play different roles in pluripotency induction (Supplementary Figure 1A-B)
Given obvious effect of FoxG1 and FoxD subgroup on reprogramming, we wondered whether FoxG1 and FoxD subgroup could substitude any Yamanaka factor especially for Oct4 which was demonstrated to be most important for induced pluripotent stem cells (iPSCs) generation

Summary

Introduction

Reprogramming somatic cells to induced pluripotent stem cells (iPSCs) by defined transcription factors is a revolutionary concept for biology and medicine, providing cellular sources for disease therapy and models for investigating roles of cell fate decision (Takahashi et al, 2007; Takahashi and Yamanaka, 2006; Yamanaka, 2020). We previously reported chromatin accessibility dynamics and found Fox relevant motif enriched significantly during mouse iPSCs induction (Cao et al, 2018; Guo et al, 2019; Li et al, 2017; Wang et al, 2019) Their functions in mouse iPSCs generation remain unclear. To address this and find novel pluripotency inducors and regulators, we here systematically studied roles of all memebrs of Fox family transcription factors in mouse pluripotency induction and found that all FoxD factors and FoxG1 accelerate iPSCs induction process from mouse fibroblasts by OSKM while FoxA and FoxO factors impede this process obviously. This study indicates the importance of Fox family transcription factors in somatic cell reprogramming and increases our knowledge of the interaction of lineage specifiers with pluripotency-associated factors

Methods

Results

Conclusion