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.
Raw and processed methylation data generated in this study can be found at GEO under the accession GSE163970.
Epigenetic analysis of Paget's disease of bone identifies differentially methylated loci that predict disease statusNCBI Gene Expression Omnibus, GSE163970.
- Omar M E Albagha
- Stuart H Ralston
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
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.
- Cheryl Ackert-Bicknell, University of Colorado, United States
© 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.
Spermatogenesis in the Drosophila male germline proceeds through a unique transcriptional program controlled both by germline-specific transcription factors and by testis-specific versions of core transcriptional machinery. This program includes the activation of genes on the heterochromatic Y chromosome, and reduced transcription from the X chromosome, but how expression from these sex chromosomes is regulated has not been defined. To resolve this, we profiled active chromatin features in the testes from wildtype and meiotic arrest mutants and integrate this with single-cell gene expression data from the Fly Cell Atlas. These data assign the timing of promoter activation for genes with germline-enriched expression throughout spermatogenesis, and general alterations of promoter regulation in germline cells. By profiling both active RNA polymerase II and histone modifications in isolated spermatocytes, we detail widespread patterns associated with regulation of the sex chromosomes. Our results demonstrate that the X chromosome is not enriched for silencing histone modifications, implying that sex chromosome inactivation does not occur in the Drosophila male germline. Instead, a lack of dosage compensation in spermatocytes accounts for the reduced expression from this chromosome. Finally, profiling uncovers dramatic ubiquitinylation of histone H2A and lysine-16 acetylation of histone H4 across the Y chromosome in spermatocytes that may contribute to the activation of this heterochromatic chromosome.
Imaging experiments reveal the complex and dynamic nature of the transcriptional hubs associated with Notch signaling.