The long non-coding RNA <i>ROCR</i> contributes to SOX9 expression and chondrogenic differentiation of human mesenchymal stem cells

Barter, M.J.; Gómez, Rodolfo; Hyatt, Sam; Cheung, Kathleen; Skelton, Andrew; Xu, Yaobo; Clark, Ian M.; Young, David A.

doi:10.1242/dev.152504

Cited by 71 publications

(64 citation statements)

References 64 publications

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“…Pathway analysis revealed that OA loci are enriched near genes involved in skeletal development and/or associated with rare monogenic bone diseases 29 . This includes the TGFb pathway genes TGFB1, LTBP1, LTBP3 and SMAD3, and the recently identified ROCR long non-coding RNA (lncRNA) that acts upstream of SOX9 during chondrogenic differentiation 32 . New OA pathways may be identified in the near future with the publication of the first multi-ethnic OA GWAS meta-analysis study performed by the Genetics of Osteoarthritis consortium ( 33 ; https://www.genetics-osteoarthritis.…”

Section: Osteoarthritis Andcartilagementioning

confidence: 99%

“…These include long noncoding RNAs (lncRNAs), a diverse group of noncoding transcripts over 200 nt in length. Although the role of individual lncRNAs such as ROCR 32 have been investigated (reviewed in 71 ), the first study to characterise lncRNAs genome-wide in OA cartilage was published this year 54 . Ajekigbe and colleagues sought to define the lncRNA transcriptome in OA cartilage by analysing both hip and knee cartilage RNA-seq data and identified a total of 1834 lncRNAs.…”

Section: Other Non-coding Rnasmentioning

confidence: 99%

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Osteoarthritis year in review 2019: genetics, genomics and epigenetics

Reynard

Barter

2020

Osteoarthritis and Cartilage

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s u m m a r yAlthough osteoarthritis (OA) aetiology is complex, genetic, genomic and epigenetic studies published within the last decade have advanced our understanding of the molecular processes underlying this common musculoskeletal disease. The purpose of this narrative review is to highlight the key research articles within the OA genetics, genomics and epigenetics fields that were published between April 2018 and April 2019. The review focuses on the identification of new OA genetic risk loci, genomics techniques that have been used for the first time in human cartilage and new publicly available databases, and datasets that will aid OA functional studies.Fifty-six new OA susceptibility loci were identified by two large scale genome wide association study meta-analyses, increasing the number of genome-wide significant risk loci to 90. OA risk variants are enriched near genes involved in skeletal development and morphology, and show genetic overlap with height, hip shape, bone area and developmental dysplasia of the hip. Several functional studies of OA loci were published, including a genome-wide analysis of genetic variation on cartilage gene expression. A specialised data portal for exploring cross-species skeletal transcriptomic datasets has been developed, and the first use of cartilage single cell RNAseq analysis reported. This year also saw the systematic identification of all microRNAs, long non-coding RNAs and circular RNAs expressed in human OA cartilage. Putative transcriptional regulatory regions have been mapped in human chondrocytes genome-wide, providing a dataset that will facilitate the prioritisation and characterisation of OA genetic and epigenetic loci.

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Section: Osteoarthritis Andcartilagementioning

confidence: 99%

Section: Other Non-coding Rnasmentioning

confidence: 99%

Osteoarthritis year in review 2019: genetics, genomics and epigenetics

Reynard

Barter

2020

Osteoarthritis and Cartilage

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“…This scaffold-free model produces a cartilaginous disc which expresses matrix components such as type II collagen and sulphated glycosaminoglycans. Chondrogenic genes such as SOX9 have been shown to be induced during the differentiation of hMSCs using this established and reproducible model of chondrogenesis [6,18,19].…”

Section: Chromatin State Changes During Chondrogenesismentioning

confidence: 94%

“…Gene expression during chondrogenesis is in part regulated by dynamic epigenetic mechanisms such as DNA methylation and histone modifications [3,4]. MicroRNAs (miRNAs) and long non-coding RNAs (lncRNAs) also play a role in chondrogenesis [5][6][7]. Genome-wide histone modification changes have been observed during in vitro differentiation of MSCs into chondrocytes [8].…”

Section: Introductionmentioning

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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“…It has a regulatory role in a variety of physiological and pathological processes. Many lncRNAs were identified in cartilage, such as lncRNA-HIT and ROCR (25). In addition, several lines of evidence suggest that lncRNAs play a role in OA.…”

Section: Introductionmentioning

confidence: 99%

Overexpression of Long Non-Coding RNA AP001505.9 Inhibits Dedifferentiation in Human Hyaline Chondrocyte

Chen

Liu

et al. 2020

Preprint

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Background: Autologous chondrocyte implantation (ACI) requires a large number ofhuman hyaline chondrocytes. Unfortunately, human hyaline chondrocytes oftenundergo dedifferentiation in vitro. Long non-coding RNAs (lncRNA) play aregulatory role in gene expression in many pathological and physiological processes.However, their role in human hyaline chondrocyte dedifferentiation remains unclear.This study aimed to investigate the expression profiles of lncRNAs in human hyalinechondrocyte dedifferentiation.Methods: Human hyaline chondrocytes were cultured in vitro and screened for theoccurrence of dedifferentiation using real-time quantitative PCR (qPCR),immunofluorescence, and western blotting. The expression profiles of lncRNAs andmRNAs during dedifferentiation were analyzed by microarray analysis and real-timeqPCR. We used pellet culture to redifferentiate chondrocytes and the expression ofrelated lncRNAs were assessed. The function of lncRNA AP001505.9(ENST00000569966) was determined by overexpression, fluorescence in situhybridization, competing endogenous RNA (ceRNA) analysis, and double luciferaselabeling.Results: We probed human hyaline chondrocytes dedifferentiation and identified 334upregulated and 381 downregulated lncRNAs. The expression of downregulatedlncRNA AP001505.9 in dedifferentiation was reversed by pellet culture. Theoverexpression of AP001505.9 inhibited dedifferentiation by promoting theexpression of SRY-Box transcription factor 9 (SOX-9) and inhibiting the expressionof type I collagen (COL1) both in vitro and in vivo.Conclusion: This study reveals for the first time the expression profiles of lncRNAsin human hyaline chondrocyte dedifferentiation, thereby providing a new perspectivefor exploring the potential mechanism of chondrocyte dedifferentiation.

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The long non-coding RNA ROCR contributes to SOX9 expression and chondrogenic differentiation of human mesenchymal stem cells

Cited by 71 publications

References 64 publications

Osteoarthritis year in review 2019: genetics, genomics and epigenetics

Osteoarthritis year in review 2019: genetics, genomics and epigenetics

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

Overexpression of Long Non-Coding RNA AP001505.9 Inhibits Dedifferentiation in Human Hyaline Chondrocyte

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