Insm1 regulates the development of mTECs and immune tolerance

TheInsm1gene encodes a zinc finger protein with known functions in neuroendocrine cells and neurons. Here we characterized the expression and function ofInsm1in medullary thymic epithelial cells (mTECs).Insm1is co-expressed with Aire in majority of Insm1 or Aire positive cells, while a few Insm1 positive cells did not express Aire. Mutation ofInsm1impair the expression ofAireand the generation of normal numbers of Aire-expressing mTECs during development. We detected downregulation of genes that expressed specifically in Aire-expressing mTEC and mimetic cells inInsm1mutant mTECs. Conversely, whenInsm1was overexpressed in thymic epithelial cellsin vivo, the size of the mTECs compartment was enlarged and the expression ofAireand genes expressed specifically in the neuroendocrine mimetic cells were increased. Mechanistically, Insm1 bound DNA in mTECs and the majority of the Insm1 binding sites were co-occupied by Aire. These Insm1 binding sites were enriched on super-enhancer regions and thus may contributed to remoted regulation. Both, mice with a thymus-specific mutation inInsm1or nude mice transplanted withInsm1mutant thymus, displayed autoimmune responses in multiple peripheral tissues. Together, our data demonstrate a role of Insm1 in development of mTECs and immune tolerance.