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Identification of a novel, methylation-dependent, RUNX2 regulatory region associated with osteoarthritis risk

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.

Publication metadata

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


DOI: 10.1093/hmg/ddy257

PubMed id: 30010910


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Funder referenceFunder name
20771VERSUS Arthritis (formerly Arthritis Research UK)
JXR 10641