This study aims to link aberrant endogenous retroviruses (ERVs) activation and osteoarthritis (OA) progression by comparing the chromatin accessibility and transcriptomic landscapes of diseased or intact joint tissues of OA patients. We performed ERVs-centric analysis on published ATAC-seq and RNA-seq data from OA patients’ cartilage tissues. Here, we compared the outer region of the lateral tibial plateau, representing intact cartilage, to the inner region of the medial tibial plateau, representing damaged cartilage. In addition, cartilage tissue sections from OA patients and post-traumatic OA mouse models were assayed for global H3K9me3 abundance through immunohistochemistry staining. Chromatin accessibility and transcription of ERVs, particularly from evolutionarily "intermediate age" ERVs families (ERV1 and ERVL), were enriched and elevated in OA cartilage. This integrative analysis suggests that H3K9me3-related heterochromatin loss might be mechanistically connected to ERV activation in OA tissue. We further verified that global H3K9me3 levels were reduced in diseased cartilage relative to intact tissue in OA patients and injury-induced OA mice. The findings suggest a compelling hypothesis that the loss of H3K9me3, either due to aging or cellular stressors, may lead to ERVs reactivation that contributes to tissue inflammation and OA progression. This study unveils the intricate relationship between epigenetic alterations, ERVs activation, and OA, paving the way for potential therapeutic interventions targeting these pathogenic mechanisms.

中文翻译：

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H3K9me3 缺失和 ERV 激活是骨关节炎进展和膝关节衰老的标志


本研究旨在通过比较 OA 患者患病或完整关节组织的染色质可及性和转录组景观，将异常内源性逆转录病毒 (ERV) 激活与骨关节炎 (OA) 进展联系起来。我们对来自 OA 患者软骨组织的已发表 ATAC-seq 和 RNA-seq 数据进行了以 ERVs 为中心的分析。在这里，我们将代表完整软骨的外侧胫骨平台的外部区域与代表受损软骨的内侧胫骨平台的内部区域进行了比较。此外，通过免疫组织化学染色分析了 OA 患者和创伤后 OA 小鼠模型的软骨组织切片的整体 H3K9me3 丰度。 ERV 的染色质可及性和转录，特别是来自进化上的“中龄”ERV 家族（ERV1 和 ERVL），在 OA 软骨中得到富集和升高。这一综合分析表明，H3K9me3 相关的异染色质丢失可能在机制上与 OA 组织中的 ERV 激活有关。我们进一步证实，在 OA 患者和损伤诱导的 OA 小鼠中，相对于完整组织，患病软骨中的整体 H3K9me3 水平降低。研究结果提出了一个令人信服的假设，即由于衰老或细胞应激源而导致的 H3K9me3 缺失可能会导致 ERV 重新激活，从而导致组织炎症和 OA 进展。这项研究揭示了表观遗传改变、ERV 激活和 OA 之间的复杂关系，为针对这些致病机制的潜在治疗干预措施铺平了道路。