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| Status |
Public on Aug 29, 2022 |
| Title |
Functional genomics in primary T cells and monocytes identifies mechanisms by which genetic susceptibility loci influence systemic sclerosis risk |
| Organism |
Homo sapiens |
| Experiment type |
Expression profiling by high throughput sequencing
Genome binding/occupancy profiling by high throughput sequencing
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| Summary |
Systemic sclerosis (SSc) is a complex autoimmune disease with a strong genetic component. However, most of the causal genes associated to the disease are still unknown because associated variants affect mostly non-coding intergenic elements of the genome. The challenge in the post-GWAS era is to use functional genomics to translate the genetic findings into a better understanding of the disease, particularly by using disease-relevant cell types. We linked SSc-associated loci to 39 new potential target genes and confirm 7 previously known genes. We highlight novel causal genes, such as CXCR5 as the most probable candidate gene for the DDX6 locus. Some previously known SSc associated genes such as IRF8, STAT4, or CD247 interestingly showed cell type specific interactions. We also identified 15 potential drug targets already in use in other similar immune-mediated diseases that could be repurposed for SSc treatment. Furthermore, we observed that interactions are directly correlated with the expression of important genes implicated in cell type specific pathways and find evidence that chromatin conformation is linked to genotype.Our study reveals potential causal genes for SSc-associated loci, some of them acting in a cell type specific manner, suggesting novel biological mechanisms that might mediate SSc pathogenesis.
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| Overall design |
Promoter capture Hi-C (pCHi-C) and RNA sequencing experiments were performed in a total of 30 CD4+ T cells and CD14+ monocytes samples from 10 SSc patients and 5 healthy controls to link SSc-associated variants with their target genes, followed by differential expression and differential interaction analyses between cell types. We also aimed to identify potential drugs that could be repurposed for its use in SSc.
NOTE FROM SUBMITTER: Data generated from patient samples. Only processed data files have been uploaded as raw data can be used to re-identify patients.
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| Contributor(s) |
González-Serna D, Shi C, Kerick M, Hankinson J, Ding J, McGovern A, Tutino M, Villanueava Martin G, Ortego-Centeno N, Luis Callejas J, Martin J, Orozco G |
| Citation(s) |
36281738 |
| |
| Submission date |
Aug 26, 2022 |
| Last update date |
Nov 28, 2022 |
| Contact name |
chenfu shi |
| E-mail(s) |
chenfu.shi@manchester.ac.uk
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| Organization name |
the university of manchester
|
| Street address |
AV Hill Building, Upper Brook Street, room 1.023
|
| City |
Manchester |
| ZIP/Postal code |
M13 9PT |
| Country |
United Kingdom |
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| Platforms (2) |
| GPL20301 |
Illumina HiSeq 4000 (Homo sapiens) |
| GPL24676 |
Illumina NovaSeq 6000 (Homo sapiens) |
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| Samples (34)
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| Relations |
| BioProject |
PRJNA874014 |
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