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Identification of TMEM129, encoding a ubiquitin-protein ligase, as an effector gene of osteoarthritis genetic risk

BACKGROUND: Osteoarthritis is highly heritable and genome-wide studies have identified single nucleotide polymorphisms (SNPs) associated with the disease. One such locus is marked by SNP rs11732213 (T > C). Genotype at rs11732213 correlates with the methylation levels of nearby CpG dinucleotides...

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Autores principales: Brumwell, Abby, Aubourg, Guillaume, Hussain, Juhel, Parker, Eleanor, Deehan, David J., Rice, Sarah J., Loughlin, John
Formato: Online Artículo Texto
Lenguaje:English
Publicado: BioMed Central 2022
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Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9358880/
https://www.ncbi.nlm.nih.gov/pubmed/35941660
http://dx.doi.org/10.1186/s13075-022-02882-y
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author Brumwell, Abby
Aubourg, Guillaume
Hussain, Juhel
Parker, Eleanor
Deehan, David J.
Rice, Sarah J.
Loughlin, John
author_facet Brumwell, Abby
Aubourg, Guillaume
Hussain, Juhel
Parker, Eleanor
Deehan, David J.
Rice, Sarah J.
Loughlin, John
author_sort Brumwell, Abby
collection PubMed
description BACKGROUND: Osteoarthritis is highly heritable and genome-wide studies have identified single nucleotide polymorphisms (SNPs) associated with the disease. One such locus is marked by SNP rs11732213 (T > C). Genotype at rs11732213 correlates with the methylation levels of nearby CpG dinucleotides (CpGs), forming a methylation quantitative trait locus (mQTL). This study investigated the regulatory activity of the CpGs to identify a target gene of the locus. METHODS: Nucleic acids were extracted from the articular cartilage of osteoarthritis patients. Samples were genotyped, and DNA methylation was quantified by pyrosequencing at 14 CpGs within a 259-bp interval. CpGs were tested for enhancer effects in immortalised chondrocytes using a reporter gene assay. DNA methylation at the locus was altered using targeted epigenome editing, with the impact on gene expression determined using quantitative polymerase chain reaction. RESULTS: rs11732213 genotype correlated with DNA methylation at nine CpGs, which formed a differentially methylated region (DMR), with the osteoarthritis risk allele T corresponding to reduced levels of methylation. The DMR acted as an enhancer and demethylation of the CpGs altered expression of TMEM129. Allelic imbalance in TMEM129 expression was identified in cartilage, with under-expression of the risk allele. CONCLUSIONS: TMEM129 is a target of osteoarthritis genetic risk at this locus. Genotype at rs11732213 impacts DNA methylation at the enhancer, which, in turn, modulates TMEM129 expression. TMEM129 encodes an enzyme involved in protein degradation within the endoplasmic reticulum, a process previously implicated in osteoarthritis. TMEM129 is a compelling osteoarthritis susceptibility target. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s13075-022-02882-y.
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spelling pubmed-93588802022-08-10 Identification of TMEM129, encoding a ubiquitin-protein ligase, as an effector gene of osteoarthritis genetic risk Brumwell, Abby Aubourg, Guillaume Hussain, Juhel Parker, Eleanor Deehan, David J. Rice, Sarah J. Loughlin, John Arthritis Res Ther Research BACKGROUND: Osteoarthritis is highly heritable and genome-wide studies have identified single nucleotide polymorphisms (SNPs) associated with the disease. One such locus is marked by SNP rs11732213 (T > C). Genotype at rs11732213 correlates with the methylation levels of nearby CpG dinucleotides (CpGs), forming a methylation quantitative trait locus (mQTL). This study investigated the regulatory activity of the CpGs to identify a target gene of the locus. METHODS: Nucleic acids were extracted from the articular cartilage of osteoarthritis patients. Samples were genotyped, and DNA methylation was quantified by pyrosequencing at 14 CpGs within a 259-bp interval. CpGs were tested for enhancer effects in immortalised chondrocytes using a reporter gene assay. DNA methylation at the locus was altered using targeted epigenome editing, with the impact on gene expression determined using quantitative polymerase chain reaction. RESULTS: rs11732213 genotype correlated with DNA methylation at nine CpGs, which formed a differentially methylated region (DMR), with the osteoarthritis risk allele T corresponding to reduced levels of methylation. The DMR acted as an enhancer and demethylation of the CpGs altered expression of TMEM129. Allelic imbalance in TMEM129 expression was identified in cartilage, with under-expression of the risk allele. CONCLUSIONS: TMEM129 is a target of osteoarthritis genetic risk at this locus. Genotype at rs11732213 impacts DNA methylation at the enhancer, which, in turn, modulates TMEM129 expression. TMEM129 encodes an enzyme involved in protein degradation within the endoplasmic reticulum, a process previously implicated in osteoarthritis. TMEM129 is a compelling osteoarthritis susceptibility target. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s13075-022-02882-y. BioMed Central 2022-08-08 2022 /pmc/articles/PMC9358880/ /pubmed/35941660 http://dx.doi.org/10.1186/s13075-022-02882-y Text en © The Author(s) 2022 https://creativecommons.org/licenses/by/4.0/Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) . The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/ (https://creativecommons.org/publicdomain/zero/1.0/) ) applies to the data made available in this article, unless otherwise stated in a credit line to the data.
spellingShingle Research
Brumwell, Abby
Aubourg, Guillaume
Hussain, Juhel
Parker, Eleanor
Deehan, David J.
Rice, Sarah J.
Loughlin, John
Identification of TMEM129, encoding a ubiquitin-protein ligase, as an effector gene of osteoarthritis genetic risk
title Identification of TMEM129, encoding a ubiquitin-protein ligase, as an effector gene of osteoarthritis genetic risk
title_full Identification of TMEM129, encoding a ubiquitin-protein ligase, as an effector gene of osteoarthritis genetic risk
title_fullStr Identification of TMEM129, encoding a ubiquitin-protein ligase, as an effector gene of osteoarthritis genetic risk
title_full_unstemmed Identification of TMEM129, encoding a ubiquitin-protein ligase, as an effector gene of osteoarthritis genetic risk
title_short Identification of TMEM129, encoding a ubiquitin-protein ligase, as an effector gene of osteoarthritis genetic risk
title_sort identification of tmem129, encoding a ubiquitin-protein ligase, as an effector gene of osteoarthritis genetic risk
topic Research
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9358880/
https://www.ncbi.nlm.nih.gov/pubmed/35941660
http://dx.doi.org/10.1186/s13075-022-02882-y
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