https://orcid.org/0000-0002-2647-6619
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Abstract
Aims: The genetic association between Behçet’s disease susceptibility and IL-10 has been confirmed in multiple cohorts, but the underlying mechanism of this association remains unclear. Materials & methods: We combined public resources and laboratory experiments (electrophoretic mobility shift assays, chromatin immunoprecipitation, luciferase reporter gene and CRISPR/Cas9 genome editing) to analyze transcription factor binding and enhancer activity controlling IL-10 expression. Results & conclusion: The T allele of noncoding rs3024490 within super-enhancer elements is able to specifically bind TBX1 and, in turn, promotes the enhancer activity and increased expression of IL-10. However, a relative deficiency in TBX1 in Behçet’s disease patients leads to the low expression of IL-10 and increased risk of developing Behçet’s disease.
Lay abstract
Behçet’s disease is a prominant cause of blindness. Previous reports show that genetic factors are linked with this disease, although the exact genetic mechanism is unclear. Many of these genetic factors are involved in the control of the immune response, including a large family of proteins known as cytokines. Some of the cytokines are proinflammatory while others can dampen the inflammatory response. An example of the latter is the IL-10 cytokine. We found that individuals carrying a specific site in the noncoding region of the IL-10 gene had a higher risk of Behçet’s disease than other noncarriers. This study was designed to further investigate the biological mechanisms explaining the role of the specific site in the development of Behçet’s disease. The results show that this specific site affects the binding of an important transcription factor, TBX1, which reduces IL-10 production. The dysregulated control of IL-10 explains why individuals with this genetic trait are more susceptible to developing Behçet’s disease.
Graphical abstract
Supplementary data
To view the supplementary data that accompany this paper please visit the journal website at: www.tandfonline.com/doi/suppl/10.2217/epi-2021-0215
Author contributions
P Yang and H Tan conceived and designed the study. H Tan, G Su, X Tan, Y Qin, L Chen and G Yuan prepared materials and performed data analysis. H Tan wrote the paper. P Yang and A Kijlstra reviewed and edited the manuscript. All authors read and approved the manuscript.
Financial & competing interests disclosure
This study was supported by Natural Science Foundation Major International (Regional) Joint Research Project (81720108009), National Natural Science Foundation Key Program (81930023), Chongqing Outstanding Scientists Project (2019), Chongqing Chief Medical Scientist Project (2018), Chongqing Key Laboratory of Ophthalmology (CSTC, 2008CA5003) and Chongqing Science & Technology Platform and Base Construction Program (cstc2014pt-sy10002). The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.
No writing assistance was utilized in the production of this manuscript.
Ethical conduct of research
The authors state that they have obtained appropriate institutional review board approval or have followed the principles outlined in the Declaration of Helsinki for all human or animal experimental investigations. In addition, for investigations involving human subjects, informed consent has been obtained from the participants involved.
Data sharing statement
All relevant data are within the manuscript and its supporting information files.