Role of PRC2 in the stochastic expression of Aire target genes and development of mimetic cells in the thymus.

The transcriptional targets of Aire and the mechanisms controlling their expression in medullary thymic epithelial cells (mTECs) need to be clarified to understand Aire's tolerogenic function. By using a multi-omics single-cell approach coupled with deep scRNA-seq, we examined how Aire controls the transcription of a wide variety of genes in a small fraction of Aire-expressing cells. We found that chromatin repression by PRC2 is an important step for Aire to achieve stochastic gene expression. Aire unleashed the silenced chromatin configuration caused by PRC2, thereby increasing the expression of its functional targets. Besides this preconditioning for Aire's gene induction, we demonstrated that PRC2 also controls the composition of mTECs that mimic the developmental trait of peripheral tissues, i.e., mimetic cells. Of note, this action of PRC2 was independent of Aire and it was more apparent than Aire. Thus, our study uncovered the essential role of polycomb complex for Aire-mediated promiscuous gene expression and the development of mimetic cells.