背景:表观遗传变化与医学联系,社会,和环境因素与心血管和肾脏疾病,最近,癌症。代谢健康与表观遗传变化之间的机制联系才刚刚开始研究。在我们的体外和体内研究中,我们对高胰岛素血症和染色质乙酰化之间的联系进行了广泛分析;我们最"命中"是H3K9ac的染色质开放.
方法:以我们已发表的临床前研究为基础,在这里,我们对胰岛素抵抗之间的联系进行了详细分析,染色质乙酰化,和炎症使用28名女性的初始测试集和245、22和53名女性的验证集。
结果:ChIP-seq确定了胰岛素抵抗女性中编码TNFα和IL6基因的染色质乙酰化和开放。通路分析确定炎症反应基因,NFκB/TNFα信号传导,反应性细胞因子信号传导,先天免疫,和衰老。与这一发现一致,流式细胞术鉴定衰老循环外周T细胞增加。DNA甲基化分析确定了胰岛素抵抗与胰岛素抵抗加速衰老的证据代谢健康的女性。
结论:这项研究表明,胰岛素抵抗妇女的染色质乙酰化/开放增加,炎症,and,也许,加速衰老。鉴于炎症在癌症发生和发展中的作用,这些研究提供了胰岛素抵抗与癌症之间潜在的机制联系.
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.