Hyperglycemia induces a dynamic cooperativity of histone methylase and demethylase enzymes associated with gene-activating epigenetic marks that coexist on the lysine tail.
Hyperglycemia induces a dynamic cooperativity of histone methylase and demethylase enzymes associated with gene-activating epigenetic marks that coexist on the lysine tail.
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作者：
Brasacchio D;Okabe J;Tikellis C;Balcerczyk A;George P;Baker EK;Calkin AC;Brownlee M;Cooper ME;El-Osta A
糖尿病控制并发症试验 (DCCT) 和随后的糖尿病干预和并发症流行病学 (EDIC) 研究以及最近的英国前瞻性糖尿病研究 (UKPDS) 的结果表明，传统治疗和更积极治疗受试者中发生的有害终末器官效应在患者恢复正常血糖控制后 5 年以上仍持续存在，并被解释为 过去的血糖遗留问题被称为“高血糖记忆”。我们假设短暂的高血糖会介导归因于表观遗传信息变化的持续基因激活事件。使用短暂高血糖模型，通过可溶性 NFκB-p65 染色质的免疫纯化，将 NFκB-p65 基因表达与组蛋白甲基转移酶（Set7 和 SuV39h1）和赖氨酸特异性脱甲基酶（LSD1）介导的 H3K4 和 H3K9 修饰联系起来。由于环境或既往高血糖而导致的 NFκB-p65 基因持续上调与 H3K4m1 增加相关，但与 H3K4m2 或 H3K4m3 增加无关。此外，葡萄糖还被证明具有其他表观遗传效应，包括抑制 p65 启动子上的 H3K9m2 和 H3K9m3 甲基化。最后，由于先前的高血糖，最近发现的组蛋白去甲基化酶 LSD1 向 p65 启动子的募集有所增加。这些研究表明，NFκB-p65 基因的活跃转录状态与持久的表观遗传标记有关，例如 H3K4 增强和 H3K9 甲基化减少，这似乎是甲基写入和甲基擦除组蛋白酶作用的结果。
Results from the Diabetes Control Complications Trial (DCCT) and the subsequent Epidemiology of Diabetes Interventions and Complications (EDIC) Study and more recently from the U.K. Prospective Diabetes Study (UKPDS) have revealed that the deleterious end-organ effects that occurred in both conventional and more aggressively treated subjects continued to operate >5 years after the patients had returned to usual glycemic control and is interpreted as a legacy of past glycemia known as “hyperglycemic memory.” We have hypothesized that transient hyperglycemia mediates persistent gene-activating events attributed to changes in epigenetic information. Models of transient hyperglycemia were used to link NFκB-p65 gene expression with H3K4 and H3K9 modifications mediated by the histone methyltransferases (Set7 and SuV39h1) and the lysine-specific demethylase (LSD1) by the immunopurification of soluble NFκB-p65 chromatin. The sustained upregulation of the NFκB-p65 gene as a result of ambient or prior hyperglycemia was associated with increased H3K4m1 but not H3K4m2 or H3K4m3. Furthermore, glucose was shown to have other epigenetic effects, including the suppression of H3K9m2 and H3K9m3 methylation on the p65 promoter. Finally, there was increased recruitment of the recently identified histone demethylase LSD1 to the p65 promoter as a result of prior hyperglycemia. These studies indicate that the active transcriptional state of the NFκB-p65 gene is linked with persisting epigenetic marks such as enhanced H3K4 and reduced H3K9 methylation, which appear to occur as a result of effects of the methyl-writing and methyl-erasing histone enzymes.