The transcriptional repressor AEBP2 is indispensable for the epigenetic control of mimetic thymic epithelial cell differentiation and central self-tolerance induction

The polycomb repressive complex 2 (PRC2) catalyses the addition of H3K27me3 marks to chromatin and thus modifies gene repression controlling the differentiation and function of medullary TECs (mTECs). The zinc finger protein AEBP2 physically interacts with PRC2 as a non-essential core component of the complex, yet its precise role in TEC biology remains untested. Here, we demonstrate that a TEC-targeted loss of AEBP2 expression in mice increases TEC and total thymic cellularity yet unexpectedly impairs the differentiation and maintenance of mimetic TEC subtypes. AEBP2-deficient mTECs display H3K27me3-dependent modifications in chromatin accessibility which compromises the capacity to promiscuously express tissue-restricted genes (TRGs). Consequently, severe lymphocytic infiltrates are observed in peripheral tissues as a result of flawed central T cell tolerance induction. Taken together, these findings highlight the essential, context-dependent role of AEBP2 in TEC differentiation and function via its impact on chromatin structure, transcriptional regulation, and developmental programming.