Session Type: ACR Poster Session C
Session Time: 9:00AM-11:00AM
Background/Purpose: Genome-wide association studies (GWAS) have revealed that the large majority of disease-associated single nucleotide polymorphisms (SNPs) are located in the non-coding regions of the genome. Genetic variation in the genomic regulatory landscape likely plays a crucial role in the pathology of disease. Non-coding variants associated with disease can influence the expression of long intergenic non-coding RNAs (lincRNAs), which in turn function in the control of protein-coding gene expression. Here, we investigate the function of two independent serum urate-associated signals in the genomic region of MAF (musculoaponeurotic fibrosarcoma oncogene homolog) and cis-located lincRNAs. MAF encodes a poorly understood transcription factor and is one of >30 loci associated with serum urate levels by GWAS and also associated with the risk of gout.
Publicly available databases accessed were serum urate GWAS summary statistics from Köttgen et al (2013), the Contextualize Developmental SNPs using 3D Information (CoDeS3D) algorithm, the NepheQTL database and expression quantitative trait loci (eQTL) data from the Genotype Tissue Expression (GTEx) database. Luciferase, siRNA knockdown assays and quantitative PCR were done in HEK293 cells. Chromatin immunoprecipitation was performed in HEPG2 cells with b-globin and ABCC6 as negative and positive controls, respectively. Enhancer assays were done in zebrafish using the ZED vector and cloning allele-specific fragments.
Results: Serum urate-associated variants rs4077450 and rs4077451 lie within an enhancer that forms long-range interactions with loci encoding lincRNAs LINC01229 and MAFTRR. We demonstrate that rs4077450 and rs4077451 can differentially regulate enhancer activity. Serum urate associated variants are also associated with expressed quantitative trait loci (eQTL) in LINC01229 and MAFTRR, which are both strongly co-expressed with the closest protein-coding gene MAF. We show that the enhancer region marked by rs4077450 and rs4077451 drives expression in the zebrafish pronephros, recapitulating endogenous MAF expression. Depletion of MAFTRR and LINC01229 in HEK293 cells leads to increased MAF expression.
Conclusion: Collectively, our results are consistent with the hypotheses that serum urate associated variants at the MAF locus mediate long-range transcriptional regulation of lincRNAs LINC01229 and MAFTRR, which in turn repress the expression of MAF.
To cite this abstract in AMA style:Leask M, Merriman TR, Dowdle A, Salvesen H, Topless R, Fadason T, Wei W, Schierding W, O'Sullivan J, Horsfield J. Non-Coding Urate-Associated Variants Function in a Conserved Lincrna Regulatory Domain That Alters MAF transcription [abstract]. Arthritis Rheumatol. 2018; 70 (suppl 10). https://acrabstracts.org/abstract/non-coding-urate-associated-variants-function-in-a-conserved-lincrna-regulatory-domain-that-alters-maf-transcription/. Accessed July 11, 2020.
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