OVOL2 suppresses epithelial to mesenchymal transition to maintain postnatal thymic epithelial cells necessary for T cell development

Thymic epithelial cells (TECs) begin to develop embryonically in mice and humans, expand in number through the stage of puberty, and then stabilize for a period before declining during early adulthood. We identified a mechanism by which TEC numbers and function are maintained postnatally, discovered through a mouse genetic screen for altered immune cell development. A viable missense allele (C120Y) of Ovol2 resulted in lymphopenia, in which T cell development was compromised by loss of medullary TECs and dysfunction of cortical TECs. OVOL2 is an essential regulator of epithelial to mesenchymal transition (EMT), and we show that the epithelial identity of TECs is subverted towards a mesenchymal state in OVOL2-deficient mice. We document global changes in chromatin accessibility correlated with gene expression, particularly affecting genes involved in epithelial and mesenchymal cell proliferation and differentiation. OVOL2 regulates chromatin accessibility by inhibiting the BRAF-HDAC complex; OVOL2 competes with RCOR1 for binding to the lysine demethylase LSD1 to inhibit LSD1-mediated H3K4me2 demethylation. Thus, OVOL2 controls the epigenetic landscape of TECs to prevent EMT, enforcing TEC identity to support T cell development in thymus.