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Lookup NU author(s): Dr Sarah RiceORCiD, Guillaume Aubourg, Dr Tony Sorial, Dr David Almarza Gomez, Maria Tselepi, Professor David Deehan, Dr Louise Reynard, Professor John LoughlinORCiD
This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).
Osteoarthritis (OA) is a common, multifactorial and polygenic skeletal disease which, in its severest form, requires joint replacement surgery to restore mobility and to relieve chronic pain. Using tissues from the articulating joints of 260 OA patients, and a range of in vitro experiments, including CRISPR-Cas9, we have characterised an intergenic regulatory element. Here, genotype at an OA risk locus correlates with differential DNA methylation, and with altered gene expression of both a transcriptional regulator (RUNX2), and a chromatin remodelling protein (SUPT3H). RUNX2 is a strong candidate for OA susceptibility, with its encoded protein being essential for skeletogenesis and healthy joint function. The OA risk locus includes SNPs located within and flanking the differentially methylated region (DMR). The OA association SNP, rs10948172, demonstrates particularly strong correlation with methylation, and two intergenic SNPs falling within the DMR (rs62435998 and rs62435999) demonstrate genetic and epigenetic effects on the regulatory activity of this region. We therefore posit that the OA signal mediates its effect by modulating the methylation of the regulatory element, which then impacts on gene expression, with RUNX2 being the principal target. Our study highlights the interplay between DNA methylation, OA genetic risk, and the downstream regulation of genes critical to normal joint function.
Author(s): Rice SJ, Aubourg G, Sorial AK, Almarza D, Tselepi M, Deehan DJ, Reynard LN, Loughlin J
Publication type: Article
Publication status: Published
Journal: Human Molecular Genetics
Year: 2018
Volume: 27
Issue: 19
Pages: 3464-3474
Print publication date: 01/10/2018
Online publication date: 10/08/2018
Acceptance date: 03/07/2018
Date deposited: 17/07/2018
ISSN (print): 0964-6906
ISSN (electronic): 1460-2083
Publisher: Oxford University Press
URL: https://doi.org/10.1093/hmg/ddy257
DOI: 10.1093/hmg/ddy257
PubMed id: 30010910
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