Integrative Analysis of the Myc and E2F pathway Reveal the Roles for microRNAs in Cell Fate Control

Abstract

Cancer is a disease state that arises as a result of multiple alterations in signaling pathways that are critical for making key cell fate decisions in normal cells. Understanding how these pathways operate under normal circumstances, therefore, is crucial for comprehensive understanding of tumorigenic process. With Myc and E2F pathways being central components for controlling cell proliferation, an important property that defines a cancer cell, as well as expanding roles for microRNAs(miRNA) in control of gene expression, we asked if we may better understand the underlying regulatory (transcription factor, microRNA) structure that contribute to Myc and E2F pathway activities. Through integrative analysis of mRNA and miRNA expression profile, we observe a distinct regulatory pattern in which, in the case of Myc pathway, Myc-induced miRNAs were contributing to the repression of negative regulators of cell cycle, including PTEN, while in case of E2F pathway, E2F-induced miRs were forming an incoherent Feed-Forward Loop(iFFL) with a number of E2F-induced genes including cyclin E. We further demonstrate through functional studies, as well as through single cell imaging of gene expression dynamics that miRNAs, depending on the context of either Myc or E2F pathway, play distinct roles in ensuring that cell fate decisions relevant to these pathways are properly executed.