目的: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。
方法:我们对已发表的来自OA患者软骨组织的ATAC-seq和RNA-seq数据进行了以ERV为中心的分析。这里,我们比较了外侧胫骨平台(oLT)的外部区域,代表完整的软骨,到内侧胫骨平台(IMT)的内部区域,代表受损的软骨。此外,通过免疫组织化学(IHC)染色测定来自OA患者和创伤后OA小鼠模型的软骨组织切片的总体H3K9me3丰度。
结果:染色质可及性和ERV的转录,特别是来自进化上的“中年”ERV家族(ERV1和ERVL),在OA软骨中富集和升高。这种综合分析表明,与H3K9me3相关的异染色质损失可能与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,患病软骨中的总体H3K9me3水平降低。
结论:研究结果表明了一个令人信服的假设,即由于衰老或细胞压力因素,H3K9me3的丢失,可能导致ERV再激活,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之间的复杂关系,ERV激活,OA,为针对这些致病机制的潜在治疗干预铺平了道路。
OBJECTIVE: 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.
METHODS: 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.
RESULTS: 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.
CONCLUSIONS: 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.