Chinese Academy of Sciences Key laboratory for Computational Biology, Chinese Academy of Sciences-Max Planck Partner Institute for Computational Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, 320 Yue Yang Road, Shanghai, 200031, China.
Aging Cell. 2012 Dec;11(6):1055-64. doi: 10.1111/acel.12007. Epub 2012 Oct 18.
Epigenetic modifications are critical determinants of cellular and developmental states. Epigenetic changes, such as decreased H3K27me3 histone methylation on insulin/IGF1 genes, have been previously shown to modulate lifespan through gene expression regulation. However, global epigenetic changes during aging and their biological functions, if any, remain elusive. Here, we examined the histone modification H3K4 dimethylation (H3K4me2) in the prefrontal cortex of individual rhesus macaques at different ages by chromatin immunoprecipitation, followed by deep sequencing (ChIP-seq) at the whole genome level. Through integrative analysis of the ChIP-seq profiles with gene expression data, we found that H3K4me2 increased at promoters and enhancers globally during postnatal development and aging, and those that correspond to gene expression changes in cis are enriched for stress responses, such as the DNA damage response. This suggests that metabolic and environmental stresses experienced by an organism are associated with the progressive opening of chromatin. In support of this, we also observed increased expression of two H3K4 methyltransferases, SETD7 and DPY30, in aged macaque brain.
表观遗传修饰是细胞和发育状态的关键决定因素。先前的研究表明，表观遗传变化，如胰岛素/IGF1 基因上 H3K27me3 组蛋白甲基化的减少，可以通过基因表达调控来调节寿命。然而，衰老过程中的全基因组表观遗传变化及其生物学功能仍然难以捉摸。在这里，我们通过染色质免疫沉淀，随后进行全基因组水平的深度测序（ChIP-seq），检测了不同年龄的恒河猴前额叶皮层中的组蛋白修饰 H3K4 二甲基化（H3K4me2）。通过将 ChIP-seq 图谱与基因表达数据进行综合分析，我们发现 H3K4me2 在出生后发育和衰老过程中在启动子和增强子上整体增加，并且与顺式基因表达变化相对应的是富含应激反应的区域，如 DNA 损伤反应。这表明生物体经历的代谢和环境应激与染色质的逐渐开放有关。支持这一观点的是，我们还观察到在老年猕猴大脑中两种 H3K4 甲基转移酶 SETD7 和 DPY30 的表达增加。
