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Insm1 regulates the development of mTECs and immune tolerance

Wehuai Tao, Yiqiu Wei, Zhihuan Ye, Jianxue Wang, Weixin Yang, Guoxing Yu, View ORCID ProfileJieyi Xiong, View ORCID ProfileShiqi Jia
doi: https://doi.org/10.1101/2023.01.14.524041
Wehuai Tao
1The First Affiliated Hospital of Jinan University, Guangzhou, China
2The Guangdong-Hong Kong-Macao Joint University Laboratory of Metabolic and Molecular Medicine, Jinan University, Guangzhou, China
3The Institute of Clinical Medicine, Jinan University, Guangzhou, China
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Yiqiu Wei
1The First Affiliated Hospital of Jinan University, Guangzhou, China
2The Guangdong-Hong Kong-Macao Joint University Laboratory of Metabolic and Molecular Medicine, Jinan University, Guangzhou, China
3The Institute of Clinical Medicine, Jinan University, Guangzhou, China
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Zhihuan Ye
1The First Affiliated Hospital of Jinan University, Guangzhou, China
2The Guangdong-Hong Kong-Macao Joint University Laboratory of Metabolic and Molecular Medicine, Jinan University, Guangzhou, China
3The Institute of Clinical Medicine, Jinan University, Guangzhou, China
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Jianxue Wang
1The First Affiliated Hospital of Jinan University, Guangzhou, China
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Weixin Yang
1The First Affiliated Hospital of Jinan University, Guangzhou, China
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Guoxing Yu
1The First Affiliated Hospital of Jinan University, Guangzhou, China
2The Guangdong-Hong Kong-Macao Joint University Laboratory of Metabolic and Molecular Medicine, Jinan University, Guangzhou, China
3The Institute of Clinical Medicine, Jinan University, Guangzhou, China
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Jieyi Xiong
4Max Delbrück Center for Molecular Medicine in the Helmholtz Association, Berlin, Germany
5VIB-KU Leuven Center for Cancer Biology, Leuven, Belgium
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  • ORCID record for Jieyi Xiong
  • For correspondence: shiqijia@jnu.edu.cn jieyi.xiong@kuleuven.be
Shiqi Jia
1The First Affiliated Hospital of Jinan University, Guangzhou, China
2The Guangdong-Hong Kong-Macao Joint University Laboratory of Metabolic and Molecular Medicine, Jinan University, Guangzhou, China
3The Institute of Clinical Medicine, Jinan University, Guangzhou, China
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  • ORCID record for Shiqi Jia
  • For correspondence: shiqijia@jnu.edu.cn jieyi.xiong@kuleuven.be
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Abstract

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 Statement

The authors have declared no competing interest.

Footnotes

  • section on result/discussion updated to clarify the Insm1 expressing and function in mTECs with related Fig1 and 3 revised

Copyright 
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. All rights reserved. No reuse allowed without permission.
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Posted January 23, 2023.
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Insm1 regulates the development of mTECs and immune tolerance
Wehuai Tao, Yiqiu Wei, Zhihuan Ye, Jianxue Wang, Weixin Yang, Guoxing Yu, Jieyi Xiong, Shiqi Jia
bioRxiv 2023.01.14.524041; doi: https://doi.org/10.1101/2023.01.14.524041
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Insm1 regulates the development of mTECs and immune tolerance
Wehuai Tao, Yiqiu Wei, Zhihuan Ye, Jianxue Wang, Weixin Yang, Guoxing Yu, Jieyi Xiong, Shiqi Jia
bioRxiv 2023.01.14.524041; doi: https://doi.org/10.1101/2023.01.14.524041

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