Epigenetic mechanisms of osteoarthritis risk in human skeletal development

Author:

McDonnell EuanORCID,Orr Sarah E,Barter Matthew J,Rux DanielleORCID,Brumwell AbbyORCID,Wrobel NicolaORCID,Murphy LeeORCID,Overmann Lynne M,Sorial Antony KORCID,Young David AORCID,Soul JamieORCID,Rice Sarah JORCID

Abstract

AbstractThe epigenome, including the methylation of cytosine bases at CG dinucleotides, is intrinsically linked to transcriptional regulation. The tight regulation of gene expression during skeletal development is essential, with ∼1/500 individuals born with skeletal abnormalities. Furthermore, increasing evidence is emerging to link age-associated complex genetic musculoskeletal diseases, including osteoarthritis (OA), to developmental factors including joint shape. Multiple studies have shown a functional role for DNA methylation in the genetic mechanisms of OA risk using articular cartilage samples taken from aged patients. Despite this, our knowledge of temporal changes to the methylome during human cartilage development has been limited.We quantified DNA methylation at ∼700,000 individual CpGs across the epigenome of developing human articular cartilage in 72 samples ranging from 7-21 post-conception weeks, a time period that includes cavitation of the developing knee joint. We identified significant changes in 8% of all CpGs, and >9400 developmental differentially methylated regions (dDMRs). The largest hypermethylated dDMRs mapped to transcriptional regulators of early skeletal patterning includingMEIS1andIRX1. Conversely, the largest hypomethylated dDMRs mapped to genes encoding extracellular matrix proteins includingSPON2andTNXBand were enriched in chondrocyte enhancers. Significant correlations were identified between the expression of these genes and methylation within the hypomethylated dDMRs. We further identified 811 CpGs at which significant dimorphism was present between the male and female samples, with the majority (68%) being hypermethylated in female samples.Following imputation, we captured the genotype of these samples at >5 million variants and performed epigenome-wide methylation quantitative trait locus (mQTL) analysis. Colocalization analysis identified 26 loci at which genetic variants exhibited shared impacts upon methylation and OA genetic risk. This included loci which have been previously reported to harbour OA-mQTLs (includingGDF5andALDH1A2), yet the majority (73%) were novel (including those mapping toCHST3, FGF1andTEAD1).To our knowledge, this is the first extensive study of DNA methylation across human articular cartilage development. We identify considerable methylomic plasticity within the development of knee cartilage and report active epigenomic mediators of OA risk operating in prenatal joint tissues.

Publisher

Cold Spring Harbor Laboratory

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