Center for Genome Sciences and Systems Biology, Washington University School of Medicine, St. Louis, Missouri, United States of America.
Department of Pediatrics, Washington University School of Medicine, St. Louis, Missouri, United States of America.
PLoS One. 2018 Sep 26;13(9):e0203147. doi: 10.1371/journal.pone.0203147. eCollection 2018.
The role of DNA methylation patterns in complex phenotypes remains unclear. To explore this question, we adapted our methods for rare variant analysis to characterize genome-wide murine DNA hybridization array to investigate methylation at CpG islands, shores, and regulatory elements. We have applied this platform to compare age and tissue- specific methylation differences in the brain and spleen of young and aged mice. As expected from prior studies, there are clear global differences in organ-specific, but not age-specific, methylation due mostly to changes at repetitive elements. Surprisingly, out of 200,000 loci there were only 946 differentially methylated cytosines (DMCs) between young and old samples (529 hypermethylated, 417 hypomethylated in aged mice) compared to thousands of tissue-specific DMCs. Hypermethylated loci were clustered around the promoter region of Sfi1, exon 2 of Slc11a2, Drg1, Esr1 and Foxa2 transcription factor binding sites. In particular, there were 75 hypermethylated Foxa2 binding sites across a 2.7 Mb region of chromosome 11. Hypomethylated loci were clustered around Mid1, Isoc2b and genome-wide loci with binding sites for Foxa2 and Esr1, which are known to play important roles in development and aging. These data suggest discreet tissue-independent methylation changes associated with aging processes such as cell division (Sfi1, Mid1), energy production (Drg1, Isoc2b) and cell death (Foxa2, Esr1).
DNA 甲基化模式在复杂表型中的作用尚不清楚。为了探索这个问题，我们改编了我们用于稀有变异分析的方法，以描述全基因组鼠 DNA 杂交阵列，以研究 CpG 岛、海岸和调控元件的甲基化。我们已经应用这个平台来比较年轻和年老小鼠大脑和脾脏中的年龄和组织特异性甲基化差异。正如先前研究所预期的那样，由于重复元件的变化，器官特异性但非年龄特异性的甲基化存在明显的全局差异。令人惊讶的是，在 20 万个基因座中，年轻和年老样本之间只有 946 个差异甲基化胞嘧啶（DMC）（529 个在年老小鼠中高甲基化，417 个低甲基化），而数千个组织特异性 DMC 之间存在差异。高甲基化基因座集中在 Sfi1 启动子区域、Slc11a2 外显子 2、Drg1、Esr1 和 Foxa2 转录因子结合位点周围。特别是，在 11 号染色体上 2.7Mb 区域有 75 个高甲基化的 Foxa2 结合位点。低甲基化基因座集中在 Mid1、Isoc2b 和基因组范围内的 Foxa2 和 Esr1 结合位点周围，这些基因已知在发育和衰老中发挥重要作用。这些数据表明，与细胞分裂（Sfi1、Mid1）、能量产生（Drg1、Isoc2b）和细胞死亡（Foxa2、Esr1）等衰老过程相关的离散的、组织独立的甲基化变化。
