Epigenetic Dynamics of Cell Reprogramming

TL;DR

This paper presents a comprehensive model of cell reprogramming that integrates fast and slow epigenetic processes, revealing how histone modifications influence cell state transitions and heterogeneity in reprogramming pathways.

Contribution

It introduces a novel integrated model of reprogramming dynamics that accounts for multiple temporal scales and explains experimental observations of heterogeneity and intermediary states.

Findings

Histone modifications create narrow valleys in the epigenetic landscape.

Altered histone modification mechanisms can accelerate reprogramming.

The model explains the heterogeneity of reprogramming latencies.

Abstract

Reprogramming is a process of transforming differentiated cells into pluripotent stem cells by inducing specific modifying factors in the cells. Reprogramming is a non-equilibrium process involving a collaboration at levels separated by orders of magnitude in time scale, namely transcription factor binding/unbinding, protein synthesis/degradation, and epigenetic histone modification. We propose a model of reprogramming by integrating these temporally separated processes and show that stable states on the epigenetic landscape should be viewed as a superposition of basin minima generated in the fixed histone states. Slow histone modification is responsible for the narrow valleys connecting the pluripotent and differentiated states on the epigenetic landscape, and the pathways which largely overlap with these valleys explain the observed heterogeneity of latencies in reprogramming. We show that histone dynamics also creates an intermediary state observed in experiments. A change in the mechanism of histone modification alters the pathway to bypass the barrier, thereby accelerating the reprogramming and reducing the heterogeneity of latencies.