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| Status |
Public on Mar 02, 2020 |
| Title |
The 11q13.5 immune disease risk locus contains a distal enhancer required for Treg-mediated suppression of gut inflammation [ATAC-Seq] |
| Organism |
Mus musculus |
| Experiment type |
Genome binding/occupancy profiling by high throughput sequencing
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| Summary |
Much of the genetic variation underlying susceptibility to common autoimmune and allergic diseases is concentrated within protein non-coding regulatory elements termed enhancers{Enhancer; Hsniz}. It has been difficult to assign functions to a majority of enhancers that overlap immune disease-associated variants due to their distance from the genes they regulate, our lack of understanding of the cell types in which they operate and our inability to recapitulate the biology of immune-mediated diseases in vitro. Here, using syntenic analysis and CRISPR-based mutagenesis to model enhancer function in mice, we show that a prominent human autoimmune/allergic disease risk locus at 11q13.5 contains a distal enhancer commissioned in Foxp3+ regulatory T (Treg) cells and required for Treg-mediated resistance to gut inflammation. Highly conserved binding sites within the enhancer recruit the transcription factor STAT5 to mediate interleukin (IL)-2-driven expression of Lrrc32, encoding Glycoprotein A Repetitions Predominant (GARP). Whereas disruption of the Lrrc32 gene results in loss of embryonic viability, mice lacking the enhancer (hereinafter Lrrc32 +70k) are viable but lack GARP expression on Foxp3+ Treg cells which subsequently are unable to control gut inflammation. In human Treg cells disease-risk alleles at 11q13.5 reduce levels of histone acetylation and are associated with reduced levels of LRRC32 expression. These findings define a function for the 11q13.5 risk locus in Treg-mediated immunoregulation and provide evidence of a causal involvement of Treg cells in the pathophysiology of polymorphic immune-mediated diseases at the intersection of genetics and the environment.
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| Overall design |
ATAC-Seq profiles of Foxp3EGFP+ Treg and Tconv cells derived from Lrrc32+ 70k enhancer KO and WT Foxp3-IRES-EGFP reporter animals
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| Contributor(s) |
Nasrallah R, Imianowski C, Bossini-Castillo L, Sadiyah F, Glinos D, Lozano T, Vardaka P, Nava C, Fujii H, Lugli E, Mitra S, Unutmaz D, Trynka G, Roychoudhuri R |
| Citation missing |
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| |
| Submission date |
Jan 13, 2020 |
| Last update date |
Mar 02, 2020 |
| Contact name |
Felix Krueger |
| E-mail(s) |
fkrueger@altoslabs.com
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| Organization name |
Altos Labs
|
| Department |
Bioinformatics
|
| Street address |
Granta Park
|
| City |
Cambridge |
| ZIP/Postal code |
CB21 6GP |
| Country |
United Kingdom |
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| Platforms (1) |
| GPL17021 |
Illumina HiSeq 2500 (Mus musculus) |
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| Samples (12)
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| This SubSeries is part of SuperSeries: |
| GSE143516 |
The 11q13.5 immune disease risk locus contains a distal enhancer required for Treg-mediated suppression of gut inflammation |
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| Relations |
| BioProject |
PRJNA600871 |
| SRA |
SRP241702 |
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