Cellular reprogramming dynamics follow a simple one-dimensional reaction coordinate

TL;DR

This study demonstrates that gene expression changes during cellular reprogramming follow a simple, universal one-dimensional reaction coordinate, revealing an underlying canonical trajectory that is independent of protocol specifics.

Contribution

The paper introduces a minimal reaction coordinate model for cellular reprogramming dynamics, supported by data reanalysis and Monte-Carlo simulations, providing new insights into the process.

Findings

Gene expression dynamics follow a universal one-dimensional reaction coordinate.

The reaction coordinate is protocol-independent and consistent across different reprogramming methods.

The model explains reprogramming as a barrier-crossing in an epigenetic landscape.

Abstract

Cellular reprogramming, the conversion of one cell type to another, has fundamentally transformed our conception of cell types. Cellular reprogramming induces global changes in gene expression involving hundreds of transcription factors and thousands of genes and understanding how cells globally alter their gene expression profile during reprogramming is an open problem. Here we reanalyze time-series data on cellular reprogramming from differentiated cell types to induced pluripotent stem cells (iPSCs) and show that gene expression dynamics during reprogramming follow a simple one-dimensional reaction coordinate. This reaction coordinate is independent of both the time it takes to reach the iPSC state as well as the details of experimental protocol used. Using Monte-Carlo simulations, we show that such a reaction coordinate emerges naturally from epigenetic landscape models of cell identity where cellular reprogramming is viewed as a "barrier-crossing" between the starting and ending cell fates. The model also provides gene-level insight into reprogramming dynamics and resolves a debate in the stem cell field about the different phases of reprogramming dynamics. Overall, our analysis and model suggest that gene expression dynamics during reprogramming follow a canonical trajectory consistent with the idea of an "optimal path" in gene expression space for reprogramming.