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

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.

本研究采用转座酶可及性染色质高通量测序检测法（Assay for Transposase-Accessible Chromatin with high throughput sequencing，ATAC-seq），绘制骨关节炎（OA）患者膝关节关节软骨的可及性染色质全景。我们共鉴定出109215个软骨可及性染色质区域，其中71%被注释为增强子。将上述区域与遗传学数据及DNA甲基化数据整合分析后，我们确定了潜在的骨关节炎相关增强子及其推定靶基因。此外，通过与RNA测序（RNA-seq）数据整合分析，我们对骨关节炎中表观基因组与转录组水平均发生改变的基因完成了特征解析。这些基因富集于调控骨化及间充质干细胞（MSC）分化的通路。一致性结果显示，骨关节炎中差异可及的区域富集于间充质干细胞特异性增强子，以及参与成骨细胞分化的转录因子家族基序。综上，本研究证实了对临床组织直接进行染色质谱分析可为疾病提供全面的表观遗传学信息，并提出了具备转化潜力的候选基因及增强子。