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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.
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.
31Background: Osteoarthritis (OA) is a common joint disorder with increasing impact 32 in an aging society; however, there is no cure or effective treatments so far due to lack 33 of sufficient understanding of its pathogenesis. While genome-wide association studies 34 (GWAS) and DNA methylation profiling identified many non-coding loci associated 35 to OA, the interpretation of them remains challenging. 36Methods: Here, we employed Assay for Transposase-Accessible Chromatin with high 37 throughput sequencing (ATAC-seq) to map the accessible chromatin landscape in 38 articular knee cartilage of OA patients and to identify the chromatin signatures relevant 39 to OA. 40 Results:We identified 109,215 accessible chromatin regions in cartilage and 71% of 41 these regions were annotated as enhancers. We found these accessible chromatin 42 regions are enriched for OA GWAS single nucleotide polymorphisms (SNPs) and OA 43 differentially methylated loci, implying their relevance to OA. By linking these 44 enhancers to their potential target genes, we have identified a list of candidate enhancers 45 that may be relevant to OA. Through integration of ATAC-seq data with RNA-seq data, 46we identified genes that are altered both at epigenomic and transcriptomic levels. These 47 enriched for mesenchymal stem cell-specific enhancers and motifs of transcription 50 factor families involved in osteoblast differentiation (e.g. bZIP and ETS). 51 Conclusions: This study marks the first investigation of accessible chromatin 52 landscape on clinically relevant hard tissues and demonstrates how accessible 53 chromatin profiling can provide comprehensive epigenetic information of a disease. 54 Our analyses provide supportive evidence towards the model of endochondral 55 ossification-like cartilage-to-bone conversion in OA knee cartilage, which is consistent 56 with the OA characteristic of thicker subchondral bone. The identified OA-relevant 57 genes and their enhancers may have a translational potential for diagnosis or drug 58 targets. 59 60 Keywords 61 osteoarthritis, epigenomics, enhancer, ATAC-seq, endochondral ossification. 62 63 Background 64Osteoarthritis (OA) is a degenerative joint disease [1,2] that is one of the most common 65 causes of chronic disability in the world [3,4], of which the knee OA is the most 66 common. Main features of OA include cartilage degradation, subchondral bone 67 thickening, joint space narrowing and osteophytes formation [5], resulting in stiffness, 68 swelling, and pain in the joint. Currently available treatments are either pain relief or 69 joint function improvement by strengthening the supporting muscles. However, OA 70 progression ultimately leads to costly total joint replacement surgery, making it a 71 growing global health burden. 72Although the causes of OA are not well understood, risk factors such as age, 73 weight, gender, and genetic factors have been identified [4]. Several models for OA 74 initiation, such as mechanical injury, inflammatory mediators from synovium, defects 75 4 in meta...
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