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| Status |
Public on Jul 03, 2024 |
| Title |
CRISPR-Cas screen in ILC2 identifies Mef2d as a regulator of GATA3 and type-2 immunity [ATAC-Seq] |
| Organism |
Mus musculus |
| Experiment type |
Genome binding/occupancy profiling by high throughput sequencing
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| Summary |
Group 2 innate lymphoid cells (ILC2s) orchestrate tissue homeostasis, allergic disorders and anti-helminth protective immunity through their production of cytokines. However, their rarity has hampered high-throughput genetic screening approaches to uncover novel ILC2 regulators in an unbiased manner. We combined expansion of progenitors from multi-reporter mouse strains with optimised ILC differentiation cultures to perform CRISPR-Cas9 screens for regulators of ILC2 development and function. Mef2d emerged as a critical regulator of GATA3 and IL-13, and was essential for type-2 immunity as demonstrated by conditional Mef2d-deficient mice, including a Boolean-ILC2-Cre (BIC) mouse strain developed to enable ILC2-specific gene deletion. Mechanistically, Mef2d bound and transcriptionally repressed the Zc3h12a locus encoding the endonuclease Regnase-1, a negative regulator of IL-33 receptor (ST2) and GATA3 expression, thereby promoting IL-33-mediated ILC2 proliferation and cytokine production. Notably, in ILC2s Mef2d also acted downstream of leukotriene C4-induced calcium-mediated signalling to translocate NFAT1 to the nucleus to promote type-2 gene transcription. These Mef2d-mediated pathways converge and feedback to potentiate type-2 immunity.
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| Overall design |
Primary mouse ATAC-seq data is generated using ex vivo expanded mouse ILC2s purified from IL-25 and IL-2/anti-IL-2-treated mice. Genomic accessibility between Il7rCre versus Mef2dIL7RKO mice were compared.
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| Citation(s) |
38935708 |
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| Submission date |
Sep 01, 2023 |
| Last update date |
Aug 09, 2024 |
| Contact name |
Ana Ferreira |
| Organization name |
MRC - Laboratory of Molecular Biology
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| Street address |
Francis Crick Avenue, Cambridge Biomedical Campus
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| City |
Cambridge |
| ZIP/Postal code |
CB2 0QH |
| Country |
United Kingdom |
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| Platforms (1) |
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| Samples (4)
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| This SubSeries is part of SuperSeries: |
| GSE242147 |
CRISPR-Cas screen in ILC2 identifies Mef2d as a regulator of GATA3 and type-2 immunity |
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| Relations |
| BioProject |
PRJNA1011860 |
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