ACR Meeting Abstracts

ACR Meeting Abstracts

Abstract Number: 2740

Takayasu Arteritis Associated Risk Locus in IL6 Represses the Anti-inflammatory Gene GPNMB Through Chromatin Looping and Recruiting MEF2-HDAC Complex

Xiufang Kong 1 and Amr Sawalha2, 1University of Michigan & Fudan University, Ann Arbor, MI, 2University of Pittsburgh & University of Michigan, Pittsburgh, PA

Meeting: 2019 ACR/ARP Annual Meeting

Keywords: , , ,

Session Information

Date: Tuesday, November 12, 2019

Title: 5T088: Genetics, Genomics & Proteomics (2738–2743)

Session Type: ACR Abstract Session

Session Time: 2:30PM-4:00PM

Background/Purpose: Previous work has revealed a genetic association between Takayasu arteritis and a non-coding genetic variant in an enhancer region within IL6 (rs2069837 A/G). The risk allele in this variant (allele A) has a protective effect against chronic viral infection and cancer. The goal of this study was the characterize the functional consequences of this disease-associated risk locus.

Methods: A combination of experimental and bioinformatics tools were used to mechanistically understand the effects of the disease-associated genetic locus in IL6. These included electrophoretic mobility shift assay (EMSA), DNA affinity precipitation assays followed by mass spectrometry and western blotting, luciferase reporter assays, and chromosome conformation capture (3C) to identify chromatin looping in the IL6 locus. Both cell lines and peripheral blood primary monocyte-derived macrophages were used.

Results: We identified the monocyte/macrophage anti-inflammatory gene GPNMB, ~520kb from IL6, as a target gene regulated by rs2069837. We revealed preferential recruitment of myocyte enhancer factor 2-histone deacetylase (MEF2-HDAC) repressive complex to the Takayasu arteritis risk allele. Further, we demonstrated suppression of GPNMB expression in monocyte-derived macrophages from healthy individuals with the AA compared to AG genotype, which was reversed by histone deacetylase inhibition. Our data show that the risk allele in rs2069837 represses the expression of GPNMB by recruiting MEF2-HDAC complex, enabled through a long-range intra-chromatin looping. Suppression of this anti-inflammatory gene might mediate increased susceptibility in Takayasu arteritis and enhance protective immune responses in chronic infection and cancer.

Conclusion: Takayasu arteritis disease risk locus in IL6 might increase disease susceptibility by suppression of the anti-inflammatory gene GPNMB, which is located about 520kb away, through chromatin looping and recruitment of MEF2-HDAC epigenetic repressive complex. Our data highlight long-range chromatin interactions in functional genomic and epigenomic studies in autoimmunity.

A proposed model for the regulatory mechanism of rs2069837 on the expression of GPNMB. The Takayasu arteritis risk allele A at this SNP preferentially recruits MEF2 and thereby HDAC proteins compared to the G allele resulting in a repressive effect by weakening the enhancer function of this locus. CTCF binding downstream of this SNP mediates the interaction between this locus to the regulatory locus in GPNMB, where a CTCF binding site also exists. The differential binding of MEF2-HADAC complex between A and G results in differential expression of GPNMB, with inhibited expression in the presence of risk allele A. Inhibiting GPNMB suppresses M2 macrophage polarization and enhances of M1 polarization and overexpression of pro-inflammatory cytokines.

Disclosure: X. Kong, None; A. Sawalha, None.

To cite this abstract in AMA style:

Kong X, Sawalha A. Takayasu Arteritis Associated Risk Locus in IL6 Represses the Anti-inflammatory Gene GPNMB Through Chromatin Looping and Recruiting MEF2-HDAC Complex [abstract]. Arthritis Rheumatol. 2019; 71 (suppl 10). https://acrabstracts.org/abstract/takayasu-arteritis-associated-risk-locus-in-il6-represses-the-anti-inflammatory-gene-gpnmb-through-chromatin-looping-and-recruiting-mef2-hdac-complex/. Accessed .

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