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| Status |
Public on Oct 25, 2023 |
| Title |
Ikaros is a principal regulator of Aire+ mTEC homeostasis, thymic mimetic cell diversity, and central tolerance [Tuft cell RNA-seq] |
| Organism |
Mus musculus |
| Experiment type |
Expression profiling by high throughput sequencing
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| Summary |
The zinc-finger transcription factor Ikaros (Ikzf1) modulates key gene expression programs important for hematopoietic development, and coding mutations in IKZF1 are found in patients with immunodeficiency, leukemia, and autoimmunity. While Ikaros has a well-established function in hematopoiesis, its role in other cell types is less well defined. Here, we uncover new functions for Ikaros in thymic epithelial lineage development and show that Ikzf1 expression in medullary thymic epithelial cells (mTECs) is required for both Autoimmune Regulator positive (Aire+) mTEC development and tissue-specific antigen (TSA) gene expression. Accordingly, TEC-specific deletion of Ikzf1 in mice results in a profound decrease in Aire+ mTECs, a global loss of TSA gene expression, and the development of autoimmunity. Moreover, Ikaros shapes thymic mimetic cell diversity and its deletion results in a dramatic expansion of thymic tuft cells and muscle-like mTECs and a loss of other Aire-dependent mimetic populations. Single-cell analysis reveals Ikaros modulates core transcriptional programs in TECs that correlate with the observed cellular changes. Our findings highlight a previously undescribed role for Ikaros in regulating epithelial lineage development and function, and suggest that failed thymic central tolerance could contribute to the autoimmunity seen in humans with IKZF1 mutations.
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| Overall design |
To investigate the differential gene expression of thymic tuft cells between Foxn1-Cre(-) Ikzf1fl/fl mice and Foxn1-Cre(+) Ikzf1fl/fl mice. We generated conditional Foxn1 conditional KO mice and FACS sorted L1CAM+ tuft cells and performed DE analysis on the two mice genotypes.
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| Contributor(s) |
Sin J, Sucharov Costa J, Waterfield MR |
| Citation(s) |
37889983 |
| |
| Submission date |
Jul 21, 2023 |
| Last update date |
Jan 24, 2024 |
| Contact name |
Jun Hyung Sin |
| E-mail(s) |
junhyung.sin@ucsf.edu
|
| Phone |
4242419276
|
| Organization name |
University of California, San Francisco
|
| Department |
Pediatrics
|
| Lab |
Waterfield
|
| Street address |
513 Parnassus Ave S-1076
|
| City |
San Francisco |
| State/province |
CA |
| ZIP/Postal code |
94143 |
| Country |
USA |
| |
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| Platforms (1) |
| GPL21103 |
Illumina HiSeq 4000 (Mus musculus) |
|
| Samples (6)
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| This SubSeries is part of SuperSeries: |
| GSE238150 |
Ikaros is a principal regulator of Aire+ mTEC homeostasis, thymic mimetic cell diversity, and central tolerance |
|
| Relations |
| BioProject |
PRJNA997348 |
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