糖尿病,一种以高血糖为特征的慢性疾病,与明显加速的并发症有关,包括糖尿病肾病(DKD),增加发病率和死亡率。高血糖和其他与糖尿病相关的环境因素,如营养过剩,久坐的生活方式和高脂血症可引起表观遗传变化。单独工作或与遗传因素一起工作,这些表观遗传变化,在没有改变基础DNA序列的情况下发生,可以改变病理生理基因的表达并损害相关靶细胞/器官的功能,导致糖尿病并发症,如DKD。值得注意的是,即使在葡萄糖正常化后,一些高血糖诱导的表观遗传变化仍存在于靶细胞/组织中,导致持续的并发症,尽管血糖控制,所谓的代谢记忆。来自体外的新证据,体内动物模型和糖尿病受试者的临床试验确定了代谢记忆和表观遗传变化(包括DNA甲基化)之间的明确关联,组蛋白修饰,染色质结构,和关键基因座处的非编码RNA。靶向这些持续的表观遗传变化和/或由它们调节的分子可以作为减弱的宝贵机会,或者消除代谢记忆,这对预防并发症进展至关重要。这里,我们回顾了迄今为止被确定为与糖尿病并发症相关的这些细胞/组织特异性表观遗传学变化,尤其是DKD,以及针对表观遗传学来解决代谢记忆的现状。我们还讨论了当前研究中的局限性,包括需要更多的(epi)全基因组研究,使用多个表观遗传标记和组学数据集进行综合分析,和代谢记忆的机械评估。考虑到表观基因组学的巨大技术进步,遗传学,测序,测序以及来自临床队列的基因组数据集的可用性,未来几年,这一领域可能会取得相当大的进展。
Diabetes, a chronic disease characterized by hyperglycemia, is associated with significantly accelerated complications, including diabetic kidney disease (DKD), which increases morbidity and mortality. Hyperglycemia and other diabetes-related environmental factors such as overnutrition, sedentary lifestyles, and hyperlipidemia can induce epigenetic changes. Working alone or with genetic factors, these epigenetic changes that occur without alterations in the underlying DNA sequence, can alter the expression of pathophysiological genes and impair functions of associated target cells/organs, leading to diabetic complications like DKD. Notably, some hyperglycemia-induced epigenetic changes persist in target cells/tissues even after glucose normalization, leading to sustained complications despite glycemic control, so-called metabolic memory. Emerging evidence from in vitro and in vivo animal models and clinical trials with subjects with diabetes identified clear associations between metabolic memory and epigenetic changes including DNA methylation, histone modifications, chromatin structure, and noncoding RNAs at key loci. Targeting such persistent epigenetic changes and/or molecules regulated by them can serve as valuable opportunities to attenuate, or erase metabolic memory, which is crucial to prevent complication progression. Here, we review these cell/tissue-specific epigenetic changes identified to-date as related to diabetic complications, especially DKD, and the current status on targeting epigenetics to tackle metabolic memory. We also discuss limitations in current studies, including the need for more (epi)genome-wide studies, integrative analysis using multiple epigenetic marks and Omics datasets, and mechanistic evaluation of metabolic memory. Considering the tremendous technological advances in epigenomics, genetics, sequencing, and availability of genomic datasets from clinical cohorts, this field is likely to see considerable progress in the upcoming years.