Chromatin accessibility landscape of articular knee cartilage reveals aberrant enhancer regulation in osteoarthritis

Osteoarthritis (OA) is a common joint disorder with increasing impact in an aging society. While genetic and transcriptomic analyses have revealed some genes and non-coding loci associated to OA, the pathogenesis remains incompletely understood. Chromatin profiling, which provides insight into gene...

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Bibliographic Details
Published in:Scientific reports 2018-10, Vol.8 (1), p.15499-13, Article 15499
Main Authors: Liu, Ye, Chang, Jen-Chien, Hon, Chung-Chau, Fukui, Naoshi, Tanaka, Nobuho, Zhang, Zhenya, Lee, Ming Ta Michael, Minoda, Aki
Format: Article
Language:English
Subjects:
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Aging
Arthritis
Cartilage diseases
Chromatin
DNA methylation
Enhancers
Gene regulation
Genetic analysis
Humanities and Social Sciences
Knee
Mesenchyme
multidisciplinary
Next-generation sequencing
Ossification
Osteoarthritis
Osteoblastogenesis
Ribonucleic acid
RNA
Science
Science (multidisciplinary)
Stem cells
Transposase
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Summary:Osteoarthritis (OA) is a common joint disorder with increasing impact in an aging society. While genetic and transcriptomic analyses have revealed some genes and non-coding loci associated to OA, the pathogenesis remains incompletely understood. Chromatin profiling, which provides insight into gene regulation, has not been reported in OA mainly due to technical difficulties. Here, we employed Assay for Transposase-Accessible Chromatin with high throughput sequencing (ATAC-seq) to map the accessible chromatin landscape in articular knee cartilage of OA patients. We identified 109,215 accessible chromatin regions for cartilages, of which 71% were annotated as enhancers. By overlaying them with genetic and DNA methylation data, we have determined potential OA-relevant enhancers and their putative target genes. Furthermore, through integration with RNA-seq data, we characterized genes that are altered both at epigenomic and transcriptomic levels in OA. These genes are enriched in pathways regulating ossification and mesenchymal stem cell (MSC) differentiation. Consistently, the differentially accessible regions in OA are enriched for MSC-specific enhancers and motifs of transcription factor families involved in osteoblast differentiation. In conclusion, we demonstrate how direct chromatin profiling of clinical tissues can provide comprehensive epigenetic information for a disease and suggest candidate genes and enhancers of translational potential.
ISSN:2045-2322
2045-2322
DOI:10.1038/s41598-018-33779-z