AUTHOR=Leask Megan , Dowdle Amy , Salvesen Hamish , Topless Ruth , Fadason Tayaza , Wei Wenhua , Schierding William , Marsman Judith , Antony Jisha , O’Sullivan Justin M. , Merriman Tony R. , Horsfield Julia A. 

TITLE=Functional Urate-Associated Genetic Variants Influence Expression of lincRNAs LINC01229 and MAFTRR

JOURNAL=Frontiers in Genetics

VOLUME=9

YEAR=2019

URL=https://www.frontiersin.org/journals/genetics/articles/10.3389/fgene.2018.00733

DOI=10.3389/fgene.2018.00733

ISSN=1664-8021

ABSTRACT=<p>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 (SUA1 and SUA2) in close proximity to lincRNAs and an enhancer that reside ∼60 kb and ∼300 kb upstream of <italic>MAF</italic>, respectively. Variants within SUA1 are expression quantitative trait loci (eQTL) for <italic>LINC01229</italic> and <italic>MAFTRR</italic>, both co-expressed with <italic>MAF</italic>. We have also identified that variants within SUA1 are <italic>trans</italic>-eQTL for genes that are active in kidney- and serum urate-relevant pathways. Serum urate-associated variants <italic>rs4077450</italic> and <italic>rs4077451</italic> within SUA2 lie within an enhancer that recruits the transcription factor HNF4α and forms long range interactions with <italic>LINC01229</italic> and <italic>MAFTRR</italic>. The urate-raising alleles of <italic>rs4077450</italic> and <italic>rs4077451</italic> increase enhancer activity and associate with increased expression of <italic>LINC01229</italic>. We show that the SUA2 enhancer region drives expression in the zebrafish pronephros, recapitulating endogenous <italic>MAF</italic> expression. Depletion of <italic>MAFTRR</italic> and <italic>LINC01229</italic> in HEK293 cells in turn lead to increased <italic>MAF</italic> expression. Collectively, our results are consistent with serum urate variants mediating long-range transcriptional regulation of the lincRNAs <italic>LINC01229</italic> and <italic>MAFTRR</italic> and urate relevant genes (e.g., <italic>SLC5A8</italic> and <italic>EHHADH</italic>) in <italic>trans</italic>.</p>