Genetic and Epigenetic Fine-Tuning of TGFB1 Expression Within the Human Osteoarthritic Joint.
Journal
Arthritis & rheumatology (Hoboken, N.J.)
ISSN: 2326-5205
Titre abrégé: Arthritis Rheumatol
Pays: United States
ID NLM: 101623795
Informations de publication
Date de publication:
10 2021
10 2021
Historique:
received:
19
01
2021
accepted:
11
03
2021
pubmed:
25
3
2021
medline:
10
11
2021
entrez:
24
3
2021
Statut:
ppublish
Résumé
Osteoarthritis (OA) is an age-related disease characterized by articular cartilage degeneration. It is largely heritable, and genetic screening has identified single-nucleotide polymorphisms (SNPs) marking genomic risk loci. One such locus is marked by the G>A SNP rs75621460, downstream of TGFB1. This gene encodes transforming growth factor β1, the correct expression of which is essential for cartilage maintenance. This study investigated the regulatory activity of rs75621460 to characterize its impact on TGFB1 expression in disease-relevant patient samples (n = 319) and in Tc28a2 immortalized chondrocytes. Articular cartilage samples from human patients were genotyped, and DNA methylation levels were quantified using pyrosequencing. Gene reporter and electrophoretic mobility shift assays were used to determine differential nuclear protein binding to the region. The functional impact of DNA methylation on TGFB1 expression was tested using targeted epigenome editing. The analyses showed that SNP rs75621460 was located within a TGFB1 enhancer region, and the OA risk allele A altered transcription factor binding, with decreased enhancer activity. Protein complexes binding to A (but not G) induced DNA methylation at flanking CG dinucleotides. Strong correlations between patient DNA methylation levels and TGFB1 expression were observed, with directly opposing effects in the cartilage and the synovium at this locus. This demonstrated biologic pleiotropy in the impact of the SNP within different tissues of the articulating joint. The OA risk SNP rs75621460 impacts TGFB1 expression by modulating the function of a gene enhancer. We propose a mechanism by which the SNP impacts enhancer function, providing novel biologic insight into one mechanism of OA genetic risk, which may facilitate the development of future pharmacologic therapies.
Substances chimiques
TGFB1 protein, human
0
Transforming Growth Factor beta1
0
Banques de données
RefSeq
['GSE108301']
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
1866-1877Subventions
Organisme : Medical Research Council
ID : MR/P020941/1
Pays : United Kingdom
Organisme : Versus Arthritis
ID : 20771
Pays : United Kingdom
Organisme : Arthritis Research UK
Pays : United Kingdom
Organisme : Seventh Framework Programme
ID : 305815
Organisme : Medical Research Council
ID : JXR 10641
Pays : United Kingdom
Informations de copyright
© 2021 The Authors. Arthritis & Rheumatology published by Wiley Periodicals LLC on behalf of American College of Rheumatology.
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