GATA3-mediated chromatin reprogramming in breast cancer cells

Pioneer transcription factors bind to silent chromatin, and initiate cell fate conversion. One potential pioneer factor, GATA3, is a critical component for multiple cellular programs. GATA3 is of particular interest as it regulates gene expression in breast cancers, and low expression correlates with poor prognosis. Here we demonstrate the pioneering activity of GATA3 utilizing a cellular reprogramming system (the mesenchymal-epithelial transition) in breast cancer cells. During the epithelial transition, GATA3 catalyzes chromatin reprogramming by inducing chromatin opening, active enhancer modifications, and nucleosome remodelling. We determined that the transactivation domain is required for this chromatin reprogramming. Importantly, a mutant lacking the transactivation domain possessed the chromatin binding ability but failed to create open chromatin, suggesting binding alone is not sufficient to induce open chromatin. These data illustrate a fundamental mechanism of GATA3-mediated gene regulation, and provide evidence for a pre-engagement state of closed chromatin bound by a pioneer factor. Genome-wide mapping of chromatin state in GATA3-mediated mesenchymal-epithelial transition