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Specific isoforms of the ubiquitin ligase gene WWP2 are targets of osteoarthritis genetic risk via a differentially methylated DNA sequence

Roberts, Jack B ; Boldvig, Olivia L G ; Aubourg, Guillaume ; Kanchenapally, S Tanishq ; Deehan, David J ; Rice, Sarah J ; Loughlin, John

Arthritis research & therapy, 2024-04, Vol.26 (1), p.78-78 [Periódico revisado por pares]

England: BioMed Central Ltd

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Specific isoforms of the ubiquitin ligase gene WWP2 are targets of osteoarthritis genetic risk via a differentially methylated DNA sequence
Autor: Roberts, Jack B ; Boldvig, Olivia L G ; Aubourg, Guillaume ; Kanchenapally, S Tanishq ; Deehan, David J ; Rice, Sarah J ; Loughlin, John
Assuntos: Adult ; Analysis ; Base Sequence ; Care and treatment ; Diagnosis ; DNA ; DNA methylation ; DNA Methylation - genetics ; DNA sequencing ; Epigenetic inheritance ; Epigenetics ; Epigenome editing ; Genes ; Genetic aspects ; Genetic transcription ; Genetics ; Genomes ; Genomics ; Humans ; Ligases ; Methylation ; MicroRNA ; MicroRNAs - metabolism ; miR-140 ; Nucleotide sequencing ; Osteoarthritis ; Osteoarthritis - genetics ; Osteoarthritis - metabolism ; Protein Isoforms - metabolism ; Risk factors ; Scientific equipment and supplies industry ; Single nucleotide polymorphisms ; Transforming Growth Factor beta - metabolism ; Transforming growth factors ; Ubiquitin ; Ubiquitin - genetics ; Ubiquitin - metabolism ; Ubiquitin-Protein Ligases - genetics ; Ubiquitin-Protein Ligases - metabolism ; WWP2
É parte de: Arthritis research & therapy, 2024-04, Vol.26 (1), p.78-78
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SourceType-Scholarly Journals-1
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Descrição: Transitioning from a genetic association signal to an effector gene and a targetable molecular mechanism requires the application of functional fine-mapping tools such as reporter assays and genome editing. In this report, we undertook such studies on the osteoarthritis (OA) risk that is marked by single nucleotide polymorphism (SNP) rs34195470 (A > G). The OA risk-conferring G allele of this SNP associates with increased DNA methylation (DNAm) at two CpG dinucleotides within WWP2. This gene encodes a ubiquitin ligase and is the host gene of microRNA-140 (miR-140). WWP2 and miR-140 are both regulators of TGFβ signaling. Nucleic acids were extracted from adult OA (arthroplasty) and foetal cartilage. Samples were genotyped and DNAm quantified by pyrosequencing at the two CpGs plus 14 flanking CpGs. CpGs were tested for transcriptional regulatory effects using a chondrocyte cell line and reporter gene assay. DNAm was altered using epigenetic editing, with the impact on gene expression determined using RT-qPCR. In silico analysis complemented laboratory experiments. rs34195470 genotype associates with differential methylation at 14 of the 16 CpGs in OA cartilage, forming a methylation quantitative trait locus (mQTL). The mQTL is less pronounced in foetal cartilage (5/16 CpGs). The reporter assay revealed that the CpGs reside within a transcriptional regulator. Epigenetic editing to increase their DNAm resulted in altered expression of the full-length and N-terminal transcript isoforms of WWP2. No changes in expression were observed for the C-terminal isoform of WWP2 or for miR-140. As far as we are aware, this is the first experimental demonstration of an OA association signal targeting specific transcript isoforms of a gene. The WWP2 isoforms encode proteins with varying substrate specificities for the components of the TGFβ signaling pathway. Future analysis should focus on the substrates regulated by the two WWP2 isoforms that are the targets of this genetic risk.
Editor: England: BioMed Central Ltd
Idioma: Inglês

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Specific isoforms of the ubiquitin ligase gene WWP2 are targets of osteoarthritis genetic risk via a differentially methylated DNA sequence

Roberts, Jack B ; Boldvig, Olivia L G ; Aubourg, Guillaume ; Kanchenapally, S Tanishq ; Deehan, David J ; Rice, Sarah J ; Loughlin, John

England: BioMed Central Ltd

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