Rare-Event Sampling of Epigenetic Landscapes and Phenotype Transitions

TL;DR

This paper introduces a rare-event simulation method to efficiently analyze epigenetic landscapes and phenotype transitions in gene regulatory networks, revealing new insights into cell fate dynamics and potential reprogramming strategies.

Contribution

A novel computational pipeline inspired by metastability studies that automates the calculation and visualization of gene network landscapes and transitions, overcoming inefficiencies of traditional stochastic simulations.

Findings

Identified rare phenotypes in pluripotency networks.

Revealed transition paths and timescales among cell states.

Transition probabilities are sensitive to kinetic parameters.

Abstract

Stochastic simulation has been a powerful tool for studying the dynamics of gene regulatory networks, particularly in terms of understanding how cell-phenotype stability and fate-transitions are impacted by noisy gene expression. However, gene networks often have dynamics characterized by multiple attractors. Stochastic simulation is often inefficient for such systems, because most of the simulation time is spent waiting for rare, barrier-crossing events to occur. We present a rare-event simulation-based method for computing epigenetic landscapes and phenotype-transitions in metastable gene networks. Our computational pipeline was inspired by studies of metastability and barrier-crossing in protein folding, and provides an automated means of computing and visualizing essential stationary and dynamic information that is generally inaccessible to conventional simulation. Applied to a network model of pluripotency in Embryonic Stem Cells, our simulations revealed rare phenotypes and approximately Markovian transitions among phenotype-states, occurring with a broad range of timescales. The relative probabilities of phenotypes and the transition paths linking pluripotency and differentiation are sensitive to global kinetic parameters governing transcription factor-DNA binding kinetics. Our approach significantly expands the capability of stochastic simulation to investigate gene regulatory network dynamics, which may help guide rational cell reprogramming strategies. Our approach is also generalizable to other types of molecular networks and stochastic dynamics frameworks.