Modeling cellular differentiation and reprogramming with gene regulatory networks

Abstract

Gene expression regulation is a fundamental cellular process that enables robust functioning of cells. How different genes interact among themselves to coordinate and maintain the overall gene expression profile observed in a cell is a key question in cellular biology. However, the immense complexity arising due to the scale and the nature of gene-gene interactions often hinders obtaining a global understanding of gene regulation. In this regard, network models of gene regulation based on gene-gene interactions, commonly referred to as gene regulatory networks (GRNs), serve important purpose of describing the overall interactions within a cell and provide a systematic approach to study their global behavior. In particular, in the context of cellular differentiation and reprogramming, where regulated changes in gene expression play a crucial role, precise knowledge of a cell type-specific GRN can enable control of the eventual cell fates with potential clinical applications. In this chapter, we describe our computational methodologies that we have tailor-made with purpose of applications to cell fate control. Briefly, we introduce the process of cellular differentiation and reprogramming, describe GRNs and common strategies to model them, and, finally, introduce the concept of determinants of cellular reprogramming and differentiation. In the Methods section, we elaborate on the different steps involved in the computational pipeline, including initial gene expression data processing, characterization of prior knowledge network, algorithm to remove non-cell type-specific edges, topological characterization of the inferred network, and Boolean network simulations to mimic cellular transitions. Finally, we provide a strategy to identify determinants of cellular reprogramming and differentiation based on the proposed computational methods.