Samoilova Ekaterina M, Belopasov Vladimir V, Ekusheva Evgenia V, Zhang Chao, Troitskiy Alexander V, Baklaushev Vladimir P
Federal Research and Clinical Center of Specialized Medical Care and Medical Technologies, FMBA of Russia, 115682 Moscow, Russia.
Neurology Department, Astrakhan State Medical Academy, 414000 Astrakhan, Russia.
J Pers Med. 2021 Oct 20;11(11):1050. doi: 10.3390/jpm11111050.
This review summarizes the current understanding of the interaction between circadian rhythms of gene expression and epigenetic clocks characterized by the specific profile of DNA methylation in CpG-islands which mirror the senescence of all somatic cells and stem cells in particular. Basic mechanisms of regulation for circadian genes CLOCK-BMAL1 as well as downstream clock-controlled genes (ССG) are also discussed here. It has been shown that circadian rhythms operate by the finely tuned regulation of transcription and rely on various epigenetic mechanisms including the activation of enhancers/suppressors, acetylation/deacetylation of histones and other proteins as well as DNA methylation. Overall, up to 20% of all genes expressed by the cell are subject to expression oscillations associated with circadian rhythms. Additionally included in the review is a brief list of genes involved in the regulation of circadian rhythms, along with genes important for cell aging, and oncogenesis. Eliminating some of them (for example, ) accelerates the aging process, while the overexpression of , on the contrary, protects against age-related changes. Circadian regulators control a number of genes that activate the cell cycle (, , , , and ) and regulate histone modification and DNA methylation. Approaches for determining the epigenetic age from methylation profiles across CpG islands in individual cells are described. DNA methylation, which characterizes the function of the epigenetic clock, appears to link together such key biological processes as regeneration and functioning of stem cells, aging and malignant transformation. Finally, the main features of adult stem cell aging in stem cell niches and current possibilities for modulating the epigenetic clock and stem cells rejuvenation as part of antiaging therapy are discussed.
本综述总结了目前对基因表达昼夜节律与表观遗传时钟之间相互作用的理解，表观遗传时钟以CpG岛中特定的DNA甲基化谱为特征，反映了所有体细胞尤其是干细胞的衰老过程。本文还讨论了昼夜节律基因CLOCK - BMAL1以及下游生物钟控制基因（CCG）的基本调控机制。研究表明，昼夜节律通过对转录的精细调控发挥作用，并依赖于多种表观遗传机制，包括增强子/抑制子的激活、组蛋白和其他蛋白质的乙酰化/去乙酰化以及DNA甲基化。总体而言，细胞表达的所有基因中，高达20%的基因表达呈现与昼夜节律相关的振荡。综述中还简要列出了参与昼夜节律调控的基因，以及对细胞衰老和肿瘤发生重要的基因。去除其中一些基因（例如， ）会加速衰老过程，而相反， 的过表达则能预防与年龄相关的变化。昼夜节律调节因子控制着许多激活细胞周期的基因（ 、 、 、 、 和 ），并调节组蛋白修饰和DNA甲基化。描述了从单个细胞中CpG岛的甲基化谱确定表观遗传年龄的方法。表征表观遗传时钟功能的DNA甲基化似乎将干细胞的再生和功能、衰老和恶性转化等关键生物学过程联系在一起。最后，讨论了干细胞微环境中成年干细胞衰老的主要特征，以及作为抗衰老治疗一部分调节表观遗传时钟和使干细胞年轻化的当前可能性。
