Identification of the key epigenetic determinants of chondrocyte aging in humans (ATAC-seq)

Articular chondrocytes undergo functional changes and their regenerative potential declines with age. Although the molecular mechanisms guiding articular cartilage aging is poorly understood, DNA methylation is known to play a mechanistic role in aging. However, our understanding of DNA methylation in chondrocyte development across human ontogeny is limited. To better understand DNA methylome changes, methylation profiling was performed in human chondrocytes. This study reveals association between methylation of specific CpG sites and chondrocyte age. We also determined the putative binding targets of STAT3, a key age-patterned TF in fetal chondrocytes and genetic ablation of STAT3 induced a global genomic hypermethylation. Moreover, an epigenetic clock built for adult human chondrocytes revealed that exposure of aged adult human chondrocytes to STAT3 agonist, decreased epigenetic age. Taken together, this work will serve as a foundation to understand development and aging of chondrocytes with a new perspective for development of rejuvenation agents for synovial joints. ATAC sequencing for human fetal chondrocytes

关节软骨细胞（articular chondrocytes）会发生功能改变，且其再生潜能随年龄增长而下降。尽管调控关节软骨衰老的分子机制仍未被充分阐明，但已知DNA甲基化（DNA methylation）在衰老过程中发挥关键调控作用。然而，目前学界对人类个体发育过程中软骨细胞发育相关的DNA甲基化调控机制的认知仍十分有限。为更好地解析DNA甲基化组的动态变化，研究人员对人类软骨细胞开展了甲基化谱分析。本研究揭示了特定CpG位点（CpG site）的甲基化水平与软骨细胞年龄之间存在显著关联。此外，本研究还明确了STAT3的潜在结合靶点——STAT3是胎儿软骨细胞中关键的年龄特征性转录因子（transcription factor, TF）；同时发现STAT3的基因敲除会诱导全基因组范围的高甲基化。针对成人软骨细胞构建的表观遗传时钟（epigenetic clock）显示，将衰老的成人软骨细胞暴露于STAT3激动剂后，其表观遗传年龄会显著降低。综上，本研究为理解软骨细胞的发育与衰老过程提供了重要理论基础，同时为滑膜关节（synovial joints）年轻化治疗药物的开发提供了全新视角。本数据集包含人类胎儿软骨细胞的转座酶可及性测序（ATAC sequencing）数据。