Histone variant macroH2A1 plays an isoform-specific role in suppressing Epithelial-Mesenchymal Transition

Abstract

Epithelial-Mesenchymal Transition (EMT) is a biological program in which epithelial cells lose their characteristics of apical-basal polarity, reduce expression of intercellular adhesion proteins with neighboring cells and acquire mesenchymal properties. There are a number of signaling mechanisms that regulate EMT induction including various EMT transcription factors such as: Snail, Slug, Twist, Zeb1/2. Additionally, RNA splicing, microRNA expression, DNA methylation and histone modifications also play important roles in EMT induction. However the role of histone variants in EMT requires additional study. Understanding the role each of these signals and their crosstalk in EMT regulation is crucial to understanding this multifaceted process.;Histone variants are important for regulating a number of cellular processes, however little is known about how their properties affect EMT. Given the well-established role of macroH2A1 in stem cell differentiation and its contributions to cancer progression, we postulated that macroH2A1 may play a role in EMT, a process involving reprogramming of cellular states. In this study, we demonstrate that expression of macroH2A1 is dramatically reduced during EMT induction in immortalized human mammary epithelial cells (HMLEs). Moreover, ectopic expression of macroH2A1.1 (but not macroH2A1.2) in HMLEs can suppress EMT induction and reduce the stem cell population in HMLEs. Though ectopic expression of macroH2A1 can prevent the transition of epithelial cells to a mesenchymal state, it is not sufficient to induce EMT's reverse process Mesenchymal-Epithelial-Transition (MET). Lastly, the suppression of EMT induction is mediated by macroH2A1.1's ability to bind NAD+ ligands.;The numerous factors that regulate EMT often exhibit crosstalk that can affect each other's signaling pathways. Here we demonstrate that histone variant macroH2A1 participates in this complex regulatory network. Our results show the EMT suppression phenotype is mediated by NAD+ metabolites, which may implicate poly(ADP-ribo)sylation as a potential post-translation modification that regulates EMT signaling.