Effects of Collective Histone State Dynamics on Epigenetic Landscape and Kinetics of Cell Reprogramming.

S S Ashwin,Masaki Sasai

doi:10.1038/srep16746

Abstract

Cell reprogramming is a process of transitions from differentiated to pluripotent cell states via transient intermediate states. Within the epigenetic landscape framework, such a process is regarded as a sequence of transitions among basins on the landscape; therefore, theoretical construction of a model landscape which exhibits experimentally consistent dynamics can provide clues to understanding epigenetic mechanism of reprogramming. We propose a minimal gene-network model of the landscape, in which each gene is regulated by an integrated mechanism of transcription-factor binding/unbinding and the collective chemical modification of histones. We show that the slow collective variation of many histones around each gene locus alters topology of the landscape and significantly affects transition dynamics between basins. Differentiation and reprogramming follow different transition pathways on the calculated landscape, which should be verified experimentally via single-cell pursuit of the reprogramming process. Effects of modulation in collective histone state kinetics on transition dynamics and pathway are examined in search for an efficient protocol of reprogramming.

Highlights

Differentiated mouse cells can be reprogrammed to induced pluripotent stem cells by inducing certain proteins known as Yamanaka factors (Oct[4], Sox[2], Klf[4], and c-Myc) in the cell[1]
We first study how topology of epigenetic landscape is influenced by the collective histone state (CHS) dynamics, and discuss pathways and kinetics on the landscape
In the non-adiabatic case with ωchs = 0.05 (Fig. 3c), both differentiated and induced pluripotent stem cells (iPSC) states are stably formed, and we find the emergence of a stable intermediate state with N A ≈ N B ≈ 0

Summary

Introduction

Differentiated mouse cells can be reprogrammed to induced pluripotent stem cells (iPSC) by inducing certain proteins known as Yamanaka factors (Oct[4], Sox[2], Klf[4], and c-Myc) in the cell[1]. Analysis of the structure of epigenetic landscape so far has been based on the assumption that gene activity is determined by binding/unbinding of transcription factors (TF) as in the case of bacterial gene regulation. Two insightful models[27,32] have been proposed on how memory arises at the epigenetic level by taking long-range interactions of nucleosomes into account[27] or by modeling short-range interactions with a Potts-like model[32] Based on these observations, we refer to the collective histone state around a gene locus, which constitutes tens or more of modified histones, as the collective histone state (CHS).

Methods

Results

Conclusion