Cole John J, Robertson Neil A, Rather Mohammed Iqbal, Thomson John P, McBryan Tony, Sproul Duncan, Wang Tina, Brock Claire, Clark William, Ideker Trey, Meehan Richard R, Miller Richard A, Brown-Borg Holly M, Adams Peter D
Beatson Institute for Cancer Research and University of Glasgow, Garscube Estate, G61 1BD, UK.
MRC Human Genetics Unit, Institute of Genetics and Molecular Medicine, Western General Hospital, Crewe Road, Edinburgh, UK.
Genome Biol. 2017 Mar 28;18(1):58. doi: 10.1186/s13059-017-1185-3.
Age-associated epigenetic changes are implicated in aging. Notably, age-associated DNA methylation changes comprise a so-called aging "clock", a robust biomarker of aging. However, while genetic, dietary and drug interventions can extend lifespan, their impact on the epigenome is uncharacterised. To fill this knowledge gap, we defined age-associated DNA methylation changes at the whole-genome, single-nucleotide level in mouse liver and tested the impact of longevity-promoting interventions, specifically the Ames dwarf Prop1 mutation, calorie restriction and rapamycin.
In wild-type mice fed an unsupplemented ad libitum diet, age-associated hypomethylation was enriched at super-enhancers in highly expressed genes critical for liver function. Genes harbouring hypomethylated enhancers were enriched for genes that change expression with age. Hypermethylation was enriched at CpG islands marked with bivalent activating and repressing histone modifications and resembled hypermethylation in liver cancer. Age-associated methylation changes are suppressed in Ames dwarf and calorie restricted mice and more selectively and less specifically in rapamycin treated mice.
Age-associated hypo- and hypermethylation events occur at distinct regulatory features of the genome. Distinct longevity-promoting interventions, specifically genetic, dietary and drug interventions, suppress some age-associated methylation changes, consistent with the idea that these interventions exert their beneficial effects, in part, by modulation of the epigenome. This study is a foundation to understand the epigenetic contribution to healthy aging and longevity and the molecular basis of the DNA methylation clock.
与年龄相关的表观遗传变化与衰老有关。值得注意的是，与年龄相关的DNA甲基化变化构成了一种所谓的衰老“时钟”，这是一种强大的衰老生物标志物。然而，虽然基因、饮食和药物干预可以延长寿命，但它们对表观基因组的影响尚不清楚。为了填补这一知识空白，我们在全基因组、单核苷酸水平上定义了小鼠肝脏中与年龄相关的DNA甲基化变化，并测试了促进长寿干预措施的影响，特别是艾姆斯侏儒Prop1突变、热量限制和雷帕霉素。
在自由采食未补充食物的野生型小鼠中，与年龄相关的低甲基化在对肝功能至关重要的高表达基因的超级增强子处富集。具有低甲基化增强子的基因富含随年龄变化表达的基因。高甲基化在标记有二价激活和抑制组蛋白修饰的CpG岛处富集，并且类似于肝癌中的高甲基化。与年龄相关的甲基化变化在艾姆斯侏儒和热量限制的小鼠中受到抑制，在雷帕霉素处理的小鼠中受到更有选择性且不太特异性的抑制。
与年龄相关的低甲基化和高甲基化事件发生在基因组的不同调控特征处。不同的促进长寿干预措施，特别是基因、饮食和药物干预，抑制了一些与年龄相关的甲基化变化，这与这些干预措施部分通过调节表观基因组发挥有益作用的观点一致。本研究是理解表观遗传学对健康衰老和长寿的贡献以及DNA甲基化时钟分子基础的基础。
