Chromatin organizer ASCL1 governs gene programs in thymic epithelial cells, defining immunological self
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Immunological self-tolerance depends on the gene expression program of medullary thymic epithelial cells (mTECs), which ectopically express thousands of tissue-specific self-antigens (TSAs). Although the autoimmune regulator AIRE is essential for this process, it does not fully account for the breadth of TSA expression, suggesting the involvement of additional regulators. Thymomas—epithelial tumors of the thymus frequently associated with autoimmunity— commonly arise in adults and often retain the capacity to support thymopoiesis, providing a unique model for studying self-tolerance in humans. Using single-cell RNA sequencing of thymic epithelial cells from thymoma patients, we identified ASCL1 as a transcription factor markedly downregulated in tumor mTECs. In mice, deletion of Ascl1 in TECs induced autoimmunity without tumor development. ASCL1 exhibited pioneer factor–like activity, shaping the chromatin landscape to regulate both AIRE-dependent and -independent gene programs. Notably, combined deletion of Ascl1 and Aire in TECs of aged mice led to ectopic thymic B cell follicle formation—a hallmark of both thymoma-associated and idiopathic myasthenia gravis. These findings identify ASCL1 as a key regulator of mTEC gene expression and thymic self-tolerance, with implications for the pathogenesis of autoimmunity.
