Document Type

Article

Publication Date

4-23-2020

Keywords

JMG

JAX Source

Front Mol Biosci 2020 Apr 23; 7:54

Volume

7

First Page

54

Last Page

54

ISSN

2296-889X

PMID

32391378

DOI

https://doi.org/10.3389/fmolb.2020.00054

Grant

CA034196,GM128717,CA174584

Abstract

Epithelial-mesenchymal transition (EMT) is well established as playing a crucial role in cancer progression and being a potential therapeutic target. To elucidate the gene regulation that drives the decision making of EMT, many previous studies have been conducted to model EMT gene regulatory circuits (GRCs) using interactions from the literature. While this approach can depict the generic regulatory interactions, it falls short of capturing context-specific features. Here, we explore the effectiveness of a combined bioinformatics and mathematical modeling approach to construct context-specific EMT GRCs directly from transcriptomics data. Using time-series single cell RNA-sequencing data from four different cancer cell lines treated with three EMT-inducing signals, we identify context-specific activity dynamics of common EMT transcription factors. In particular, we observe distinct paths during the forward and backward transitions, as is evident from the dynamics of major regulators such as NF-KB (e.g., NFKB2 and RELB) and AP-1 (e.g., FOSL1 and JUNB). For each experimental condition, we systematically sample a large set of network models and identify the optimal GRC capturing context-specific EMT states using a mathematical modeling method named Random Circuit Perturbation (RACIPE). The results demonstrate that the approach can build high quality GRCs in certain cases, but not others and, meanwhile, elucidate the role of common bioinformatics parameters and properties of network structures in determining the quality of GRCs. We expect the integration of top-down bioinformatics and bottom-up systems biology modeling to be a powerful and generally applicable approach to elucidate gene regulatory mechanisms of cellular state transitions.

Comments

This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY).

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