Epigenetic analysis of Paget’s disease of bone identifies differentially methylated loci that predict disease status
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE163970 | GEO | 2021/06/03
REPOSITORIES: GEO
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Project description: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 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 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.
| S-EPMC8184208 | biostudies-literature
Project description:Paget’s disease of bone (PDB) is a chronic focal skeletal disorder that affects 2-3% of the population over the age of 60. PDB is inherited as an autosomal dominant trait with genetic heterogeneity. SQSTM1/p62 UBA domain mutation (p62P392L) is widely identified in PDB and has been shown to increase osteoclastogenesis. Further, environmental factors such as paramyxovirus are implicated in PDB and MVNP has been shown to induce Pagetic phenotype in osteoclasts. However, the molecular mechanisms underlying p62P392L and MVNP stimulation of osteoclast differentiation in PDB are unclear. We therefore determined MVNP regulated gene expression profiling during osteoclast differentiation. We identified 8.4% of genes were upregulated (> 4-fold) in MVNP transduced cells. MVNP increased integrin β3 (63 fold), NFAT activating protein (6.5 fold), OSCAR (5.5 fold), TRAF5 (8.5 fold) mRNA expression compared to empty vector (EV) transduced cells. MVNP also elevated gene expression of cytokines/growth factors such as IL-17 (18 fold), IL-1F7 (10 fold), IL-17R (4.5 fold) and IL-11 (7 fold). Interestingly, MVNP transduced cells demonstrated high level expression of signal regulatory protein beta 1 (SIRPβ1) (353 fold). SIRPβ1 has been shown to interact with DAP 12, an ITAM containing adaptor protein which plays an important role in osteoclast differentiation. Real-time PCR analysis of total RNA isolated from normal human peripheral blood monocytes transduced with MVNP confirmed upregulation of SIRPβ1 mRNA expression in the absence of RANKL stimulation. In contrast, RANKL stimulation did not alter SIRPβ1 expression in these cells. Furthermore, bone marrow mononuclear cells derived from patients with PDB showed high levels of SIRPβ1 mRNA expression compared to normal subjects. Thus, MVNP regulated gene expression profiling during osteoclast differentiation provides new insights into molecular mechanisms and therapeutic targets to control elevated osteoclast activity in PDB. Total RNA isolated from normal human bone marrow mononuclear cells transduced with EV, MVNP retroviral expression vectors and stimulated with M-CSF and RANKL for 48 h were subjected to Agilent microarray (~26,000 genes) analysis. One replicate per treatment was hybridized.
2011-09-30 | E-GEOD-29106 | biostudies-arrayexpress
Project description:Paget’s disease of bone (PDB) is a chronic focal skeletal disorder that affects 2-3% of the population over the age of 60. PDB is inherited as an autosomal dominant trait with genetic heterogeneity. SQSTM1/p62 UBA domain mutation (p62P392L) is widely identified in PDB and has been shown to increase osteoclastogenesis. Further, environmental factors such as paramyxovirus are implicated in PDB and MVNP has been shown to induce Pagetic phenotype in osteoclasts. However, the molecular mechanisms underlying p62P392L and MVNP stimulation of osteoclast differentiation in PDB are unclear. We therefore determined MVNP regulated gene expression profiling during osteoclast differentiation. We identified 8.4% of genes were upregulated (> 4-fold) in MVNP transduced cells. MVNP increased integrin β3 (63 fold), NFAT activating protein (6.5 fold), OSCAR (5.5 fold), TRAF5 (8.5 fold) mRNA expression compared to empty vector (EV) transduced cells. MVNP also elevated gene expression of cytokines/growth factors such as IL-17 (18 fold), IL-1F7 (10 fold), IL-17R (4.5 fold) and IL-11 (7 fold). Interestingly, MVNP transduced cells demonstrated high level expression of signal regulatory protein beta 1 (SIRPβ1) (353 fold). SIRPβ1 has been shown to interact with DAP 12, an ITAM containing adaptor protein which plays an important role in osteoclast differentiation. Real-time PCR analysis of total RNA isolated from normal human peripheral blood monocytes transduced with MVNP confirmed upregulation of SIRPβ1 mRNA expression in the absence of RANKL stimulation. In contrast, RANKL stimulation did not alter SIRPβ1 expression in these cells. Furthermore, bone marrow mononuclear cells derived from patients with PDB showed high levels of SIRPβ1 mRNA expression compared to normal subjects. Thus, MVNP regulated gene expression profiling during osteoclast differentiation provides new insights into molecular mechanisms and therapeutic targets to control elevated osteoclast activity in PDB.
2011-10-01 | GSE29106 | GEO
Project description:Paget’s disease of bone (PDB) is a chronic focal skeletal disorder that affects 2-3% of the population over the age of 60. PDB is inherited as an autosomal dominant trait with genetic heterogeneity. SQSTM1/p62 UBA domain mutation (p62P392L) is widely identified in PDB and has been shown to increase osteoclastogenesis. Further, environmental factors such as paramyxovirus are implicated in PDB and MVNP has been shown to induce Pagetic phenotype in osteoclasts. However, the molecular mechanisms underlying p62P392L and MVNP stimulation of osteoclast differentiation in PDB are unclear. We therefore determined p62P392L regulated gene expression profiling during osteoclast differentiation. We identified 9.7% genes were upregulated (> 4-fold) in p62P392L transduced cells. P62P392L mutant increased Integrin β3 (185 fold), integrin β5 (26 fold), IL-1α (11 fold), IL-6R (8 fold), CXCL-2 (7.5 fold), CXCL-3 (5 fold) compared to p62WT transduced cells. Furthermore, bone marrow mononuclear cells derived from patients with PDB showed high levels of SIRPβ1 mRNA expression compared to normal subjects. Thus, p62P392L mutant regulated gene expression profiling during osteoclast differentiation provides new insights into molecular mechanisms and therapeutic targets to control elevated osteoclast activity in PDB. Total RNA isolated from normal human bone marrow mononuclear cells transduced with p62EV, p62WT, p62P392L retroviral expression vectors and stimulated with M-CSF and RANKL for 48 h were subjected to Agilent microarray (~26,000 genes) analysis. One replicate per treatment was hybridized.
2011-09-30 | E-GEOD-29107 | biostudies-arrayexpress
Project description:Paget’s disease of bone (PDB) is a chronic focal skeletal disorder that affects 2-3% of the population over the age of 60. PDB is inherited as an autosomal dominant trait with genetic heterogeneity. SQSTM1/p62 UBA domain mutation (p62P392L) is widely identified in PDB and has been shown to increase osteoclastogenesis. Further, environmental factors such as paramyxovirus are implicated in PDB and MVNP has been shown to induce Pagetic phenotype in osteoclasts. However, the molecular mechanisms underlying p62P392L and MVNP stimulation of osteoclast differentiation in PDB are unclear. We therefore determined p62P392L regulated gene expression profiling during osteoclast differentiation. We identified 9.7% genes were upregulated (> 4-fold) in p62P392L transduced cells. P62P392L mutant increased Integrin β3 (185 fold), integrin β5 (26 fold), IL-1α (11 fold), IL-6R (8 fold), CXCL-2 (7.5 fold), CXCL-3 (5 fold) compared to p62WT transduced cells. Furthermore, bone marrow mononuclear cells derived from patients with PDB showed high levels of SIRPβ1 mRNA expression compared to normal subjects. Thus, p62P392L mutant regulated gene expression profiling during osteoclast differentiation provides new insights into molecular mechanisms and therapeutic targets to control elevated osteoclast activity in PDB.
2011-10-01 | GSE29107 | GEO
Project description:Background: Paget's Disease of Bone (PDB) is characterized by excessive and disorganized bone remodeling, in which bone-resorbing osteoclasts play a key role. Strong genetic components and environmental factors contribute to the etiopathogenesis of PDB. We hypothesized that dysregulated microRNA (miR) expression contributed to the osteoclast phenotype in PDB. Results: From deep sequencing, six mature miRs, miR-29b1-3p, miR-15b-5p, miR-181a-5p, let7i-3p, miR-500b-5p, and miR-1246, were found to be significantly decreased in overactive osteoclasts from the PDB patients compared to those in the healthy controls. The differential expression of the miRs was confirmed by the analysis of a larger independent cohort using qPCR. Conclusion: We identified six miRNAs whose expression were deregulated in PDB condition. Many of these miRs are known to modulate many critical aspects of osteoclast generation and function by coordinating their regulation of gene expression. Our results enhance the understanding of osteoclast biology in PDB disease
2023-09-30 | GSE174180 | GEO
Project description:Epigenetic analysis of Paget’s disease of bone identifies differentially methylated loci that predict disease status
| PRJNA688467 | ENA
Project description:This pioneering study investigated associations between DNA methylation levels and PDB severity. 100 methylation sites associated with PDB disease severity were identified, while important molecular pathways associated with disease progression were also disclosed. Importantly, DNA methylation markers to predict disease severity with high accuracy were also identified but require further validations.
2022-05-18 | GSE201322 | GEO
Project description:H2A.B is a unique histone H2A variant that only exists in mammals. Here we found that H2A.B is ubiquitously expressed in major organs. Genome-wide analysis of H2A.B in mouse ES cells shows that H2A.B is associated with methylated DNA in gene body regions. Moreover, H2A.B-enriched gene loci are actively transcribed. One typical example is that H2A.B is enriched in a set of differentially methylated regions at imprinted loci and facilitates transcription elongation. These results suggest that H2A.B positively regulates transcription elongation by overcoming DNA methylation in the transcribed region. It provides a novel mechanism by which transcription is regulated at DNA hypermethylated regions.
| S-EPMC3975057 | biostudies-literature
Project description:Paget disease of bone (PDB) is a chronic skeletal disorder with contemporary cases characterised by one or a few affected bones in individuals over 55 years of age. PDB-like changes have been noted in archaeological remains as old as Roman although accurate diagnoses and knowledge of the natural history of ancient forms of the disease are lacking. Previous macroscopic and radiographic analyses of six skeletons from a collection of 130 excavated at Norton Priory in Cheshire, UK, and dating to late Medieval times, noted unusually extensive pathological changes resembling PDB affecting up to 75% of individual skeletons. Here we report the prevalence of the disease in the collection is also remarkably high (at least 15.8% of the adult sample) with age-at-death estimations as low as 35 years. Despite these profound phenotypic differences paleoproteomic analyses identified SQSTM1/p62 (p62), a protein central to the pathological milieu of classical PDB, as one of the few non-collagenous human sequences preserved in skeletal samples, indicating that the disorder was likely an ancient precursor of contemporary PDB. Western blotting indicated abnormal migration of ancient p62 protein, with subsequent targeted proteomic analyses detecting more than 60% of the p62 primary sequence and directing sequencing analyses of ancient DNA that excluded contemporary PDB-associated SQSTM1 mutations. Together our observations indicate the ancient p62 protein is likely modified within its C-terminal ubiquitin-associated (UBA) domain. Ancient miRNAs were also remarkably well preserved in an osteosarcoma from a skeleton with extensive disease, with miR-16 expression changes consistent with that reported in contemporary PDB-associated bone tumours. Our work demonstrates the potential of proteomics to inform diagnoses of ancient disease and supports the proposal that Medieval Norton Priory was a ‘hotspot’ for an ancient form of PDB, with unusual features presumably potentiated by as yet unidentified environmental or genetic factors.
2019-04-09 | PXD011743 | Pride