Epigenetic mechanisms of osteoarthritis risk in human skeletal development.

Autor:	McDonnell E; Computational Biology Facility, University of Liverpool, MerseyBio, Crown Street, United Kingdom., Orr SE; Biosciences Institute, Newcastle University, Central Parkway, Newcastle upon Tyne, United Kingdom., Barter MJ; Biosciences Institute, Newcastle University, Central Parkway, Newcastle upon Tyne, United Kingdom., Rux D; Orthopaedic Surgery, UConn Health, Farmington, Connecticut, USA., Brumwell A; Biosciences Institute, Newcastle University, Central Parkway, Newcastle upon Tyne, United Kingdom., Wrobel N; Edinburgh Clinical Research Facility, University of Edinburgh, Edinburgh, United Kingdom., Murphy L; Edinburgh Clinical Research Facility, University of Edinburgh, Edinburgh, United Kingdom., Overmann LM; Human Developmental Biology Resource, Newcastle University, International Centre for Life, Central Parkway, Newcastle upon Tyne, United Kingdom., Sorial AK; Biosciences Institute, Newcastle University, Central Parkway, Newcastle upon Tyne, United Kingdom., Young DA; Biosciences Institute, Newcastle University, Central Parkway, Newcastle upon Tyne, United Kingdom., Soul J; Institute of Systems, Molecular and Integrative Biology, University of Liverpool, Liverpool, United Kingdom., Rice SJ; Biosciences Institute, Newcastle University, Central Parkway, Newcastle upon Tyne, United Kingdom.
Jazyk:	angličtina
Zdroj:	MedRxiv : the preprint server for health sciences [medRxiv] 2024 May 06. Date of Electronic Publication: 2024 May 06.
DOI:	10.1101/2024.05.05.24306832
Abstrakt:	The 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 including MEIS1 and IRX1 . Conversely, the largest hypomethylated dDMRs mapped to genes encoding extracellular matrix proteins including SPON2 and TNXB and 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 (including GDF5 and ALDH1A2 ), yet the majority (73%) were novel (including those mapping to CHST3, FGF1 and TEAD1 ). 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. Competing Interests: Declaration of Interests LM has received speaker and consultancy fees from Illumina. We have no other conflicting interest to declare.
Databáze:	MEDLINE
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