Epigenetic analysis of Paget's disease of bone identifies differentially methylated loci that predict disease status
Abstract
Paget's Disease of Bone (PDB) is characterized by focal increases in disorganized bone remodeling. This study aims to characterize PDB associated changes in DNA methylation profiles in patients' blood. Meta-analysis of data from the discovery and cross-validation set, each comprising of 116 PDB cases and 130 controls, revealed significant differences in DNA methylation at 14 CpG sites, 4 CpG islands, and 6 gene-body regions. These loci, including two characterized as functional through expression quantitative trait-methylation (eQTM) analysis, were associated with functions related to osteoclast differentiation, mechanical loading, immune function, and viral infection. A multivariate classifier based on discovery samples was found to discriminate PDB cases and controls from the cross-validation with a sensitivity of 0.84, specificity of 0.81, and an area under curve of 92.8%. In conclusion, this study has shown for the first time that epigenetic factors contribute to the pathogenesis of PDB and may offer diagnostic markers for prediction of the disease.
Data availability
Raw and processed methylation data generated in this study can be found at GEO under the accession GSE163970.
Article and author information
Author details
Funding
European Research Council (FP7/2007-2013)
- Omar M E Albagha
European Research Council (787270-Paget-Advance)
- Stuart H Ralston
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Ethics
Human subjects: The study was approved by the UK Multicenter Research Ethics Committee for Scotland(MREC01/0/53) and NHS Lothian, Edinburgh (08/S1104/8) ethics review committees. Allparticipants provided written informed consent.
Reviewing Editor
- Cheryl Ackert-Bicknell, University of Colorado, United States
Publication history
- Received: January 4, 2021
- Accepted: April 29, 2021
- Accepted Manuscript published: April 30, 2021 (version 1)
- Accepted Manuscript updated: May 4, 2021 (version 2)
- Version of Record published: June 7, 2021 (version 3)
Copyright
© 2021, Diboun et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
Metrics
-
- 677
- Page views
-
- 100
- Downloads
-
- 4
- Citations
Article citation count generated by polling the highest count across the following sources: Crossref, PubMed Central, Scopus.
Download links
Downloads (link to download the article as PDF)
Open citations (links to open the citations from this article in various online reference manager services)
Cite this article (links to download the citations from this article in formats compatible with various reference manager tools)
Further reading
-
- Chromosomes and Gene Expression
An evolutionary perspective enhances our understanding of biological mechanisms. Comparison of sex determination and X-chromosome dosage compensation mechanisms between the closely related nematode species C. briggsae (Cbr) and C. elegans (Cel) revealed that the genetic regulatory hierarchy controlling both processes is conserved, but the X-chromosome target specificity and mode of binding for the specialized condensin dosage compensation complex (DCC) controlling X expression have diverged. We identified two motifs within Cbr DCC recruitment sites that are highly enriched on X: 13-bp MEX and 30-bp MEX II. Mutating either MEX or MEX II in an endogenous recruitment site with multiple copies of one or both motifs reduced binding, but only removing all motifs eliminated binding in vivo. Hence, DCC binding to Cbr recruitment sites appears additive. In contrast, DCC binding to Cel recruitment sites is synergistic: mutating even one motif in vivo eliminated binding. Although all X-chromosome motifs share the sequence CAGGG, they have otherwise diverged so that a motif from one species cannot function in the other. Functional divergence was demonstrated in vivo and in vitro. A single nucleotide position in Cbr MEX can determine whether Cel DCC binds. This rapid divergence of DCC target specificity could have been an important factor in establishing reproductive isolation between nematode species and contrasts dramatically with conservation of target specificity for X-chromosome dosage compensation across Drosophila species and for transcription factors controlling developmental processes such as body-plan specification from fruit flies to mice.
-
- Chromosomes and Gene Expression
- Plant Biology
A well-established model for how plants start the process of flowering in periods of cold weather may need revisiting.