Gene suppression by PRC2 enhances the gene inductions by Aire and the development of mimetic cell populations

Aire, a transcriptional regulator whose defect results in the development of autoimmunity, controls the transcriptome in the bulk of medullary thymic epithelial cells (mTECs) including the genes for self-antigens. Mechanisms for this process, however, remained incompletely understood, especially regarding the effects of Aire in each subpopulation in mTECs. Here, we profiled mTECs from EED-cKO (EED conditional knockout mice using Foxn1-Cre, JACKSON LABORATORY #022727 and #018448) and Aire/EED-dKO (Aire EED double knockout mice, PMID: 19015306) by RamDA-seq to evaluate the association between the gene suppression by polycomb repressive complex 2 (PRC2) and the gene induction by Aire. We found that genes are suppressed by PRC2 in an Aire-independent manner in mTEC and the gene suppression by PRC2 paradoxically augments the gene inductions by Aire. Interestingly, PRC2 also suppresses the signature genes for mimetic cell populations and their development was diminished in the absence of EED. deep single-cell RNA-seq analysis of FACS-sorted thymic epithelial cells (TECs, CD45-EpCAM+Ly51-MHCIIhigh) from EED conditional knockout mice (EED-cKO) and Aire/EED double knockout mice (Aire/EED-dKO)