Genome-wide DNA methylation profile implicates potential cartilage regeneration at the late stage of knee osteoarthritis

Zhang, Y.; Fukui, Naoshi; Yahata, M.; Katsuragawa, Yozo; Tashiro, Tazuko; Ikegawa, Shiro; Lee, Ming Ta Michael

doi:10.1016/j.joca.2015.12.013

Cited by 45 publications

(45 citation statements)

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“…Our data indicates that where there was previously no evidence of methylation changes in gene promoters during OA, such as ACAN and p21WAF1/CIPl, that dynamic methylation at enhancers regulating such genes should be considered (Poschl et al , 2005; Sesselmann et al , 2009). A number of studies have also identified DNA methylation changes in OA or damaged cartilage but it remains to be determined whether these correspond to enhancer regions (den Hollander et al , 2014; Fernandez-Tajes et al , 2014; Jeffries et al , 2014; Alvarez-Garcia et al , 2016; Bonin et al , 2016; Zhang et al , 2016; Steinberg et al , 2017). The subset of chondrogenesis DMLs also significantly altered in OA become hypomethylated consistent with the cells reactivating developmental pathways (Loeser et al , 2012; Reynard, 2017).…”

Section: Discussionmentioning

confidence: 99%

DNA hypomethylation during MSC chondrogenesis occurs predominantly at enhancer regions

Barter

Bui

Cheung

et al. 2019

Preprint

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SummaryRegulation of transcription occurs in a cell type specific manner by epigenetic mechanisms including DNA methylation and histone modifications. Methylation changes during stem cell differentiation may play a key role in lineage specification. We sought to characterise DNA methylation changes during chondrogenesis of mesenchymal stem cells (MSCs) in order to further our understanding of epigenetic regulation in chondrocytes. The consequences of which has potential to improve cartilage generation for tissue engineering purposes and also to provide context for observed methylation changes in cartilage diseases such as osteoarthritis. We identified significant DNA hypomethylation during chondrogenesis including changes at many key cartilage gene loci. Importantly characterisation of significant CpG loci indicated their predominant localisation to enhancer regions. Comparison with adult cartilage and other tissue methylation profiles identified chondrocyte-specific regulatory regions. Taken together we have associated methylation at many CpGs with the chondrocyte phenotype.AbstractRegulation of transcription is determined in a cell type specific manner by epigenetic mechanisms including DNA methylation and histone modifications. Methylation changes during stem cell differentiation may play a role in lineage specification. Multipotent mesenchymal stem cell (MSC) differentiation into chondrocytes not only serves as a model for chondrocyte development but also provides an important source of cartilage for tissue engineering purposes. We sought to characterise DNA methylation changes during chondrogenesis to further understanding of epigenetic regulation but to also provide context for the changes identified during disease.DNA cytosine methylation changes during human MSC differentiation into chondrocytes were measured by Infinium 450K methylation array. Methylation changes at gene loci were contrasted with gene expression changes. Chromatin states of significant methylation loci were interpreted by intersection with chondrogenesis histone modification ChlP-seq data. Chondrogenic and cartilage specific hypomethylation was utilised in order to identify a chondrocyte methylome. Articular cartilage and tissue panel DNA methylation was compared and alterations during osteoarthritis cartilage disease classified.Significant DNA hypomethylation was identified following chondrogenic differentiation of MSCs including changes at many key cartilage gene loci. Highly upregulated genes during chondrogenesis were more likely to exhibit a reduction in DNA methylation. Characterisation of significant CpG loci indicated their predominant localisation in CpG poor regions which importantly are most likely to correspond to enhancer regions. Methylation level at certain CpGs following chondrogenesis corresponds to the level found in adult cartilage.Taken together, considerable demethylation changes to the epigenetic landscape occur during MSC chondrogenesis especially at sites marked by enhancer modifications. Comparison with other tissues, including healthy and OA cartilage, associates CpGs to the chondrocyte phenotype and provides context for changes in disease.

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Section: Discussionmentioning

confidence: 99%

DNA hypomethylation during MSC chondrogenesis occurs predominantly at enhancer regions

Barter

Bui

Cheung

et al. 2019

Preprint

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“…Aberrant DNA methylation in enhancers has been implicated in diseases such as cancer [44][45][46] and osteoarthritis (OA) [47,48].…”

Section: Discussionmentioning

confidence: 99%

Histone ChIP-Seq identifies differential enhancer usage during chondrogenesis as critical for defining cell-type specificity

Cheung

Barter

Falk

et al. 2019

Preprint

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Human mesenchymal stem cells are able to differentiate into chondrocytes, the cell type found in cartilage, making them an accessible system to study gene regulation during this process. Epigenetic mechanisms such as histone modifications and DNA methylation together with transcription factor binding play a role in activating and repressing gene expression. In this study, we investigated the genome-wide histone modification changes during chondrocyte differentiation. Integration of this data with DNA methylation and SOX9 transcription factor ChIP-seq revealed epigenetic changes at gene enhancer elements.Regions of the genome that transition from non-enhancers to enhancers in chondrocytes are enriched for SOX9 transcription factor binding sites. Luciferase reporter assays revealed that enhancer activity may be modulated by manipulating DNA methylation and SOX9 expression.This study has defined important regulatory elements in chondrocytes which could serve as targets for future mechanistic studies. AbstractEpigenetic mechanisms are known to regulate gene expression during chondrogenesis. In this study, we have characterised the epigenome during in vitro differentiation of human mesenchymal stem cells (hMSCs) into chondrocytes. Chromatin immunoprecipitation followed by next-generation sequencing (ChIP-seq) was used to assess a range of N-terminal post-transcriptional modifications (marks) to histone H3 lysines (H3K4me3, H3K4me1, H3K27ac, H3K27me3 and H3K36me3) in both hMSCs and differentiated chondrocytes.Chromatin states were characterised using histone ChIP-seq and cis-regulatory elements were identified in chondrocytes. Chondrocyte enhancers were associated with chondrogenesis related gene ontology (GO) terms. In silico analysis and integration of DNA methylation data with chondrogenesis chromatin states revealed that enhancers marked by histone marks H3K4me1 and H3K27ac were de-methylated during in vitro chondrogenesis. Similarity analysis between hMSC and chondrocyte chromatin states defined in this studywith epigenomes of cell-types defined by the Roadmap Epigenomics project revealed that enhancers are more distinct between cell-types compared to other chromatin states. Motif analysis revealed that the transcription factor SOX9 is enriched in chondrocyte enhancers.Luciferase reporter assays confirmed that chondrocyte enhancers characterised in this study exhibited enhancer activity which may be modulated by inducing DNA methylation and SOX9 overexpression. Altogether, these integrated data illustrate the cross-talk between different epigenetic mechanisms during chondrocyte differentiation.

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“…Methylation levels of some CpG sites on OA cartilage were correlated with the histopathologic disease severity score, assessed by modified Mankin score (Jeffries et al 2014). Recently, Zhang et al reported changes in DNA methylation profile of OA chondrocytes according to disease progression, with changes preferentially observed at last stage of OA (Zhang et al 2016). …”

Section: Epigenetics and Musculoskeletal Function During Agingmentioning

confidence: 99%

The epigenetic landscape of age-related diseases: the geroscience perspective

et al. 2017

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In this review, we summarize current knowledge regarding the epigenetics of age-related diseases, focusing on those studies that have described DNA methylation landscape in cardio-vascular diseases, musculoskeletal function and frailty. We stress the importance of adopting the conceptual framework of “geroscience”, which starts from the observation that advanced age is the major risk factor for several of these pathologies and aims at identifying the mechanistic links between aging and age-related diseases. DNA methylation undergoes a profound remodeling during aging, which includes global hypomethylation of the genome, hypermethylation at specific loci and an increase in inter-individual variation and in stochastic changes of DNA methylation values. These epigenetic modifications can be an important contributor to the development of age-related diseases, but our understanding on the complex relationship between the epigenetic signatures of aging and age-related disease is still poor. The most relevant results in this field come from the use of the so called “epigenetics clocks” in cohorts of subjects affected by age-related diseases. We report these studies in final section of this review.

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Genome-wide DNA methylation profile implicates potential cartilage regeneration at the late stage of knee osteoarthritis

Abstract: Our data suggested the changes in DNA methylation occurred at the late stage of OA. Pathways and networks enriched in identified DM genes highlighted potential etiologic mechanism and implicated the potential cartilage regeneration in the late stage of knee OA.

Cited by 45 publications

References 46 publications

DNA hypomethylation during MSC chondrogenesis occurs predominantly at enhancer regions

DNA hypomethylation during MSC chondrogenesis occurs predominantly at enhancer regions

Histone ChIP-Seq identifies differential enhancer usage during chondrogenesis as critical for defining cell-type specificity

The epigenetic landscape of age-related diseases: the geroscience perspective

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