Shifting epigenetic contexts influence regulatory variation and disease risk

Richard, Daniel; Capellini, Terence D.

doi:10.18632/aging.203194

Cited by 4 publications

(3 citation statements)

References 84 publications

(1 reference statement)

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“…We conclude that the DMR is actively methylated after skeletogenesis and that the effect of genotype on methylation increases with age. The WWP2 association signal may therefore be an example of antagonistic pleiotropy or genetic drift in OA, with the risk-conferring allele having a positive or neutral effect on joint formation but a negative effect on joint health as we age [39,40].…”

Section: Discussionmentioning

confidence: 99%

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

Roberts,

Boldvig,

Aubourg

et al. 2024

Preprint

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Background 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 rs34195470 and which maps to functional candidates WWP2 and microRNA-140 (miR-140). Methods Nucleic acids were extracted from adult OA (arthroplasty) and foetal cartilage. Samples were genotyped and DNA methylation (DNAm) quantified by pyrosequencing at 16 CpG dinucleotides located within a putative enhancer. 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. Results rs34195470 genotype associates with differential methylation of the CpGs, forming a methylation quantitative trait locus (mQTL). The mQTL is more pronounced in adult versus foetal cartilage. The differential methylation acts as a transcriptional regulatory intermediate between risk allele and level of WWP2 expression by targeting the full-length and N-terminal transcript isoforms of the gene. Conclusions As far as we are aware, this is the first experimental demonstration of an OA association signal targeting specific transcript isoforms of a gene. WWP2 encodes a ubiquitin ligase, with its isoforms encoding proteins with varying substrate specificities, including for components of the TGFb signaling pathway. Future analysis should focus on the substrates regulated by the WWP2 isoforms that are the targets of the genetic risk.

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Section: Discussionmentioning

confidence: 99%

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

Roberts,

Boldvig,

Aubourg

et al. 2024

Preprint

View full text Add to dashboard Cite

show abstract

Section: Discussionmentioning

confidence: 99%

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

Roberts,

Boldvig,

Aubourg

et al. 2024

Arthritis Res Ther

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Background 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. Methods 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. Results 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. Conclusions 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.

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“…Recent work on the link between age-changes in epigenetic state and effects of genetic polymorphisms on late-life disease have led to the proposition that there exists a "central trajectory for epigenetic state that reflects innate aging processes" (Boyle et al, 2012;Richard and Capellini, 2021). This idea is readily reconciled with the developmental sequence hypothesis.…”

Section: A Developmental Sequence Constraining Life History Evolution?mentioning

confidence: 99%

Epigenetic Clocks and Programmatic Aging

Gems,

Singh Virk,

de Magalhães

2023

Preprint

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The last decade has seen remarkable progress in the characterization of methylation clocks that track biological age in humans and many other mammalian species. While the biological processes of aging that underlie these clocks have remained unclear, several clues have pointed to a link to developmental mechanisms. These include the presence in the vicinity of clock CpG sites of genes that specify development, including those of the Hox (homeobox) and polycomb classes. Here we discuss how recent advances in programmatic theories of aging provide a framework within which methylation clocks can be understood as part of a developmental process of aging. This includes how such clocks evolve, how developmental mechanisms cause aging, and how they give rise to late-life disease. The combination of ideas from evolutionary biology, biogerontology and developmental biology open a path to a new discipline, that of developmental gerontology (devo-gero). Drawing on the properties of methylation clocks, we offer several new hypotheses that exemplify devo-gero thinking. We suggest that polycomb controls a trade-off between earlier developmental fidelity and later developmental plasticity. We also propose the existence of an evolutionarily-conserved developmental sequence spanning ontogenesis, adult development and aging, that both constrains and determines the evolution of aging.

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Shifting epigenetic contexts influence regulatory variation and disease risk

Cited by 4 publications

References 84 publications

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

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

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

Epigenetic Clocks and Programmatic Aging

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