Nanog, Oct4 and Tet1 interplay in establishing pluripotency.

Victor Olariu,Kim Sneppen,Cecilia Lövkvist

doi:10.1038/srep25438

Abstract

A few central transcription factors inside mouse embryonic stem (ES) cells and induced pluripotent stem (iPS) cells are believed to control the cells’ pluripotency. Characterizations of pluripotent state were put forward on both transcription factor and epigenetic levels. Whereas core players have been identified, it is desirable to map out gene regulatory networks which govern the reprogramming of somatic cells as well as the early developmental decisions. Here we propose a multiple level model where the regulatory network of Oct4, Nanog and Tet1 includes positive feedback loops involving DNA-demethylation around the promoters of Oct4 and Tet1. We put forward a mechanistic understanding of the regulatory dynamics which account for i) Oct4 overexpression is sufficient to induce pluripotency in somatic cell types expressing the other Yamanaka reprogramming factors endogenously; ii) Tet1 can replace Oct4 in reprogramming cocktail; iii) Nanog is not necessary for reprogramming however its over-expression leads to enhanced self-renewal; iv) DNA methylation is the key to the regulation of pluripotency genes; v) Lif withdrawal leads to loss of pluripotency. Overall, our paper proposes a novel framework combining transcription regulation with DNA methylation modifications which, takes into account the multi-layer nature of regulatory mechanisms governing pluripotency acquisition through reprogramming.

Highlights

A few central transcription factors inside mouse embryonic stem (ES) cells and induced pluripotent stem cells are believed to control the cells’ pluripotency
We put forward a mechanistic understanding of the regulatory dynamics which account for i) Oct[4] overexpression is sufficient to induce pluripotency in somatic cell types expressing the other Yamanaka reprogramming factors endogenously; ii) Ten-eleven translocation (Tet)[1] can replace Oct[4] in reprogramming cocktail; iii) Nanog is not necessary for reprogramming its over-expression leads to enhanced self-renewal; iv) DNA methylation is the key to the regulation of pluripotency genes; v) Lif withdrawal leads to loss of pluripotency
The computational model is based on a simple gene regulatory network, which includes possible interaction between Tet[1] and core pluripotency factors Oct[4] and Nanog during cell reprogramming and commitment[40,42]

Summary

Introduction

A few central transcription factors inside mouse embryonic stem (ES) cells and induced pluripotent stem (iPS) cells are believed to control the cells’ pluripotency. We put forward a mechanistic understanding of the regulatory dynamics which account for i) Oct[4] overexpression is sufficient to induce pluripotency in somatic cell types expressing the other Yamanaka reprogramming factors endogenously; ii) Tet[1] can replace Oct[4] in reprogramming cocktail; iii) Nanog is not necessary for reprogramming its over-expression leads to enhanced self-renewal; iv) DNA methylation is the key to the regulation of pluripotency genes; v) Lif withdrawal leads to loss of pluripotency. The pluripotent state of stem cells is maintained by the core circuitry where Oct[4], Sox[2] and Nanog regulate each other as well as their own expression and they control expression of multiple genes associated with pluripotency pathways[10,11,12]. Loss of Oct[4] expression makes ES cells commit towards trophoblast lineage[6] in vivo the pluripotency characteristics of the cells in the inner cell mass are lost in www.nature.com/scientificreports/

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