Background: Epigenetic changes link medical, social, and environmental factors with cardiovascular and kidney disease and, more recently, with cancer. The mechanistic link between metabolic health and epigenetic changes is only starting to be investigated. In our in vitro and in vivo studies, we performed a broad analysis of the link between hyperinsulinemia and chromatin acetylation; our top “hit” was chromatin opening at H3K9ac. Methods: Building on our published preclinical studies, here, we performed a detailed analysis of the link between insulin resistance, chromatin acetylation, and inflammation using an initial test set of 28 women and validation sets of 245, 22, and 53 women. Results: ChIP-seq identified chromatin acetylation and opening at the genes coding for TNFα and IL6 in insulin-resistant women. Pathway analysis identified inflammatory response genes, NFκB/TNFα-signaling, reactome cytokine signaling, innate immunity, and senescence. Consistent with this finding, flow cytometry identified increased senescent circulating peripheral T-cells. DNA methylation analysis identified evidence of accelerated aging in insulin-resistant vs. metabolically healthy women. Conclusions: This study shows that insulin-resistant women have increased chromatin acetylation/opening, inflammation, and, perhaps, accelerated aging. Given the role that inflammation plays in cancer initiation and progression, these studies provide a potential mechanistic link between insulin resistance and cancer.
背景：表观遗传变化将医学、社会及环境因素与心血管疾病、肾脏疾病乃至近期发现的癌症联系起来。代谢健康与表观遗传变化之间的机制关联研究才刚刚起步。通过体外与体内实验，我们广泛分析了高胰岛素血症与染色质乙酰化之间的关联，其中最重要的发现是H3K9ac位点的染色质开放现象。 方法：基于已发表的临床前研究，我们通过初步测试组（28名女性）及验证组（245名、22名和53名女性）对胰岛素抵抗、染色质乙酰化与炎症之间的关联进行了深入分析。 结果：染色质免疫沉淀测序分析显示，胰岛素抵抗女性中编码TNFα和IL6的基因位点出现染色质乙酰化及开放现象。通路分析识别出炎症反应基因、NFκB/TNFα信号通路、反应组细胞因子信号传导、先天免疫及衰老相关通路。与此一致的是，流式细胞术检测到衰老循环外周T细胞数量增加。DNA甲基化分析显示，与代谢健康女性相比，胰岛素抵抗女性呈现加速衰老的迹象。 结论：本研究表明胰岛素抵抗女性存在染色质乙酰化/开放程度增加、炎症水平升高，并可能伴随加速衰老现象。鉴于炎症在癌症发生与发展中的作用，这些研究为胰岛素抵抗与癌症之间的潜在机制关联提供了证据。
肿瘤(癌症)患者之家