Conserved effect of aging on DNA methylation and association with EZH2 polycomb protein in mice and humans.
Conserved effect of aging on DNA methylation and association with EZH2 polycomb protein in mice and humans.
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DOI：
10.1016/j.mad.2017.02.006
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发表时间：
2017-03
影响因子：
5.3
通讯作者：
Pandey AK
中科院分区：
文献类型：
--
作者：
Mozhui K;Pandey AK
在人类中，特定CpG位点的DNA甲基化可用于估计“表观遗传时钟”，这是衰老和健康的生物标志物。调节衰老表观基因组和保守水平的机制尚不完全清楚。我们用甲基-CpG结合结构域蛋白进行基于亲和力的富集，然后进行高通量测序（MBD-seq）以测定小鼠样品中的DNA甲基化。与先前的报道一致，衰老与CpG岛甲基化的增加有关，CpG岛可能与癌症相关基因的调控区域重叠（例如，C1 q13、Srd 5a 2和Ptk 7）。小鼠中的差异甲基化区域在人类中具有高度的序列保守性，并且甲基化模式在两个物种之间也很大程度上保守。基于人类ENCODE数据，这些位点被包括EZH 2的polycomb蛋白靶向。染色质免疫沉淀证实，这些区域在小鼠中也与EZH 2相互作用，并且随着年龄的增长，C1 q13处的EZH 2占有率可能会降低。这增加了越来越多的证据表明EZH 2是塑造衰老表观基因组的蛋白质机制的一部分。年龄依赖性CpG序列和甲基化模式的保守性表明表观遗传时钟是哺乳动物衰老的基本特征。
In humans, DNA methylation at specific CpG sites can be used to estimate the ‘epigenetic clock’, a biomarker of aging and health. The mechanisms that regulate the aging epigenome and level of conservation are not entirely clear. We performed affinity-based enrichment with methyl-CpG binding domain protein followed by high-throughput sequencing (MBD-seq) to assay DNA methylation in mouse samples. Consistent with previous reports, aging is associated with increase in methylation at CpG islands that likely overlap regulatory regions of genes that have been implicated in cancers (e.g., C1ql3, Srd5a2 and Ptk7). The differentially methylated regions in mice have high sequence conservation in humans and the pattern of methylation is also largely conserved between the two species. Based on human ENCODE data, these sites are targeted by polycomb proteins, including EZH2. Chromatin immunoprecipitation confirmed that these regions interact with EZH2 in mice as well, and there may be reduction in EZH2 occupancy with age at C1ql3. This adds to the growing evidence that EZH2 is part of the protein machinery that shapes the aging epigenome. The conservation in both sequence and methylation patterns of the age-dependent CpGs indicate that the epigenetic clock is a fundamental feature of aging in mammals.