What is the role of the histone variant macroH2A1.1 (mH2A1.1) in shaping the phenotypic identity of triple-negative breast cancer (TNBC) cells?
The principal aim of this project is to characterize the impact of mH2A1.1 on cellular plasticity of TNBC cells by analyzing its effect on gene expression, 3D genome architecture and biophysical properties.
Unlike canonical histones, variants like mH2A1.1 have distinct structures, allowing them to influence chromatin architecture and gene expression. mH2A1.1 plays a role in critical cellular processes, such as epithelial-to-mesenchymal transition (EMT) and cell metabolism. We have shown that its overexpression is associated with poor prognosis in TNBC.
We are now focusing on characterizing the molecular mechanisms that enable mH2A1.1 to function as a transcriptional regulator in TNBC cells. Notably, we found that mH2A1.1 binds to super-enhancers (SEs), in addition to gene promoters. SEs are membraneless organelles that form through Liquid-Liquid Phase Separation (LLPS), a process driven by intrinsically disordered regions in transcription factors and coactivators. Given the disordered and highly charged nature of mH2A1.1's linker domain, it is possible that it contributes to LLPS at SEs, amplifying gene expression.
Our goal is to identify the partners involved in its dual transcriptional activities, encompassing both its repressive and activating functions, as well as to explore its potential Liquid-Liquid Phase Separation (LLPS) properties, which may be key to its functional roles. At the cellular level, we are investigating the impact of mH2A1.1 on maintaining specific mesenchymal traits and the cellular plasticity of MDA-MB231 cells, and how this influences their propensity to develop metastasis.