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GEO help: Mouse over screen elements for information. |
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| Status |
Public on Feb 01, 2022 |
| Title |
A20 governs fibrosis susceptibility in bleomycin-induced mouse scleroderma model |
| Organism |
Mus musculus |
| Experiment type |
Expression profiling by high throughput sequencing
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| Summary |
In addition to autoimmune and inflammatory diseases, variants of the TNFAIP3 gene encoding A20 are also associated with systemic sclerosis (SSc). However, it remains unclear how genetic factors contribute to fibrosis in SSc, and which cell types drive disease due to SSc-specific genetic alterations. We characterized the expression and function of A20, and its negative transcriptional regulator DREAM, in patient with SSc. We found that levels of A20 were significantly reduced in SSc skin and lung biopsies, while DREAM was elevated and showed anti-correlation with A20. Mice haploinsufficient for A20, or harboring fibroblasts-specific A20 deletion, recapitulated major pathological and genomic features of SSc, whereas DREAM-null mice showed elevated A20 expression and were protected from fibrosis. In fibroblasts, A20 mitigated ex vivo profibrotic responses. An anti-fibrotic small molecule targeting the adiponectin receptors stimulated A20 expression in vitro in wildtype but not A20-deficient fibroblasts, and in bleomycin-treated mice. Thus, A20 has a novel function in negative regulation of fibroblast responses, and together with DREAM, constitutes a critical regulatory network governing the fibrotic process in SSc, suggesting that A20 and DREAM represent novel druggable targets.
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| Overall design |
We have generated A20+/- mice, by crossing A20fl/fl mice with EIIa-Cre mice generating mice with a single A20 allele, and displaying ~50% decrease in levels of A20 in multiple tissues. At 6-8 weeks of age, four female A20 +/- mice and four female wildtype mice were randomized to start treatment with s.c. bleomycin, a fibrosis inducing agent (5 mg/kg/day), or PBS given for 10 days (5 days/week). Mice were then sacrificed at day 22 and skin tissues were harvested RNA isolation and RNA sequencing.
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| Contributor(s) |
Wang W, Wei J, Abdala-Valencia H, Berdnikovs S, Bhattacharyya S, Varga J |
| Citation(s) |
36289219 |
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| Submission date |
Jan 25, 2022 |
| Last update date |
Nov 01, 2022 |
| Contact name |
Swati Bhattacharyya |
| E-mail(s) |
bhattasw@med.umich.edu
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| Phone |
734-936-5566
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| Organization name |
University of Michigan
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| Street address |
1150 W. Medical Center Drive
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| City |
Ann Arbor |
| State/province |
MI |
| ZIP/Postal code |
48109 |
| Country |
USA |
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| Platforms (1) |
| GPL19057 |
Illumina NextSeq 500 (Mus musculus) |
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| Samples (8)
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| Relations |
| BioProject |
PRJNA800403 |
| Supplementary file |
Size |
Download |
File type/resource |
| GSE194380_gene_fpmk_matrix.txt.gz |
5.0 Mb |
(ftp)(http) |
TXT |
SRA Run Selector |
| Raw data are available in SRA |
| Processed data are available on Series record |
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