Your browser doesn't support javascript.
loading
Genetic and Epigenetic Fine-Tuning of TGFB1 Expression Within the Human Osteoarthritic Joint.
Rice, Sarah J; Roberts, Jack B; Tselepi, Maria; Brumwell, Abby; Falk, Julia; Steven, Charlotte; Loughlin, John.
Afiliação
  • Rice SJ; Newcastle University and International Centre for Life, Newcastle-upon-Tyne, UK.
  • Roberts JB; Newcastle University and International Centre for Life, Newcastle-upon-Tyne, UK.
  • Tselepi M; Newcastle University and International Centre for Life, Newcastle-upon-Tyne, UK.
  • Brumwell A; Newcastle University and International Centre for Life, Newcastle-upon-Tyne, UK.
  • Falk J; Newcastle University and International Centre for Life, Newcastle-upon-Tyne, UK.
  • Steven C; Newcastle University and International Centre for Life, Newcastle-upon-Tyne, UK.
  • Loughlin J; Newcastle University and International Centre for Life, Newcastle-upon-Tyne, UK.
Arthritis Rheumatol ; 73(10): 1866-1877, 2021 10.
Article em En | MEDLINE | ID: mdl-33760378
ABSTRACT

OBJECTIVE:

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 ß1, 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.

METHODS:

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.

RESULTS:

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.

CONCLUSION:

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.
Assuntos

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Osteoartrite / Cartilagem Articular / Metilação de DNA / Polimorfismo de Nucleotídeo Único / Fator de Crescimento Transformador beta1 Tipo de estudo: Prognostic_studies Limite: Humans Idioma: En Ano de publicação: 2021 Tipo de documento: Article

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Osteoartrite / Cartilagem Articular / Metilação de DNA / Polimorfismo de Nucleotídeo Único / Fator de Crescimento Transformador beta1 Tipo de estudo: Prognostic_studies Limite: Humans Idioma: En Ano de publicação: 2021 Tipo de documento: Article