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| Status |
Public on Jun 07, 2023 |
| Title |
Sex bias in autoimmunity is driven by androgen regulation of T cell-intrinsic mechanisms |
| Organism |
Mus musculus |
| Experiment type |
Genome binding/occupancy profiling by high throughput sequencing
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| Summary |
Major autoimmune diseases such as systemic lupus erythematosus (SLE), multiple sclerosis, rheumatoid arthritis and Graves’ disease display a striking female bias, with a female-to-male incidence ratio ranging up to 9:1 in SLE. Sex hormones contribute to protection of males from autoimmunity, but precise molecular mechanisms of such protection are poorly understood. Here, we find that Androgen Receptor (AR), a nuclear receptor regulating a plethora of genes, is active in T cells during development and regulates directly genes involved in T cell activation or indirectly through regulation of other transcription factors. A gene encoding a phosphatase Ptpn22, a negative regulator of T cell receptor signaling, was found to be dependent of the presence of androgen receptor (AR) in males. Castration or deletion of AR reduced expression of Ptpn22. In a mouse model of Systemic Lupus Erythematosus (SLE), Ptpn22 deletion led to the loss of sexual dimorphism. Moreover, analysis of the regulatory regions of Ptpn22 gene revealed a highly conserved sequence that was necessary for upregulation of the gene’s expression by androgens. Mutation of this sequence in Non-Obese Diabetic (NOD) mice led to enhanced ability of T cells to cause Type 1 diabetes. Thus, PTPN22 is likely to participate in disease pathogenesis making it and other AR-regulated genes fair targets for therapeutic interventions in major autoimmune diseases.
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| Overall design |
AR ChIP-seq profiling of murine thymocytes
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| Contributor(s) |
Lee J, Yurkovetskiy L, Khan A, Chervonsky A |
| Citation missing |
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| Submission date |
Jun 05, 2023 |
| Last update date |
Jun 09, 2023 |
| Contact name |
Aly Azeem Khan |
| Organization name |
University of Chicago
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| Street address |
6045 S. Kenwood Ave.
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| City |
Chicago |
| State/province |
IL |
| ZIP/Postal code |
60637 |
| Country |
USA |
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| Platforms (1) |
| GPL17021 |
Illumina HiSeq 2500 (Mus musculus) |
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| Samples (3) |
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| Relations |
| BioProject |
PRJNA980178 |
| Supplementary file |
Size |
Download |
File type/resource |
| GSE234134_RAW.tar |
240.0 Kb |
(http)(custom) |
TAR (of TXT) |
SRA Run Selector |
| Raw data are available in SRA |
| Processed data provided as supplementary file |
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