RT Journal Article
SR Electronic
T1 Insm1 regulates the development of mTECs and immune tolerance
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 2023.01.14.524041
DO 10.1101/2023.01.14.524041
A1 Wehuai Tao
A1 Yiqiu Wei
A1 Zhihuan Ye
A1 Jianxue Wang
A1 Weixin Yang
A1 Guoxing Yu
A1 Jieyi Xiong
A1 Shiqi Jia
YR 2023
UL http://biorxiv.org/content/early/2023/01/23/2023.01.14.524041.abstract
AB The Insm1 gene encodes a zinc finger protein with known functions in neuroendocrine cells and neurons. Here we characterized the expression and function of Insm1 in medullary thymic epithelial cells (mTECs). Insm1 is co-expressed with Aire in majority of Insm1 or Aire positive cells, while a few Insm1 positive cells did not express Aire. Mutation of Insm1 impair the expression of Aire and 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 in Insm1 mutant mTECs. Conversely, when Insm1 was overexpressed in thymic epithelial cells in vivo, the size of the mTECs compartment was enlarged and the expression of Aire and 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 in Insm1 or nude mice transplanted with Insm1 mutant thymus, displayed autoimmune responses in multiple peripheral tissues. Together, our data demonstrate a role of Insm1 in development of mTECs and immune tolerance.Competing Interest StatementThe authors have declared no competing interest.