Reduced DNA methylation patterning and transcriptional connectivity define human skin aging.
Reduced DNA methylation patterning and transcriptional connectivity define human skin aging.
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DNA甲基化模式和转录连通性降低定义了人皮肤老化。
DOI：
10.1111/acel.12470
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发表时间：
2016-06
期刊：
影响因子：
7.8
通讯作者：
Lyko F
中科院分区：
文献类型：
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作者：
Bormann F;Rodríguez-Paredes M;Hagemann S;Manchanda H;Kristof B;Gutekunst J;Raddatz G;Haas R;Terstegen L;Wenck H;Kaderali L;Winnefeld M;Lyko F
表观遗传学的变化代表了一个有吸引力的机制，了解与人类衰老相关的表型变化。在基因组规模上与年龄相关的DNA甲基化变化被称为“表观遗传漂移”，但这种现象的定义特征仍有待确定。人类表皮是了解年龄相关表观遗传变化的一个很好的模型，因为它具有相当大的细胞类型同质性和众所周知的年龄相关表型。我们现在已经生成并分析了目前最大的一组人类表皮甲基化组（N = 108），使用基于阵列的450000个甲基化标记在不同年龄组中进行分析。数据分析证实，与年龄相关的甲基化差异受到局部限制，且效应大小相对较小。然而，甲基化数据可以用于预测样本供体的实际年龄，具有较高的准确性。我们还确定了不连续的甲基化变化作为老化甲基化组的一个新特征。最后，我们的分析揭示了与年龄相关的DNA甲基化模式的侵蚀，其特征是动态范围减小和全局甲基化模式异质性增加。甲基化变异性的这些变化伴随着转录网络的连接性降低。因此，我们的研究结果将表观遗传调控保真度的丧失定义为衰老表观基因组的一个关键特征。
Epigenetic changes represent an attractive mechanism for understanding the phenotypic changes associated with human aging. Age‐related changes in DNA methylation at the genome scale have been termed ‘epigenetic drift’, but the defining features of this phenomenon remain to be established. Human epidermis represents an excellent model for understanding age‐related epigenetic changes because of its substantial cell‐type homogeneity and its well‐known age‐related phenotype. We have now generated and analyzed the currently largest set of human epidermis methylomes (N = 108) using array‐based profiling of 450 000 methylation marks in various age groups. Data analysis confirmed that age‐related methylation differences are locally restricted and characterized by relatively small effect sizes. Nevertheless, methylation data could be used to predict the chronological age of sample donors with high accuracy. We also identified discontinuous methylation changes as a novel feature of the aging methylome. Finally, our analysis uncovered an age‐related erosion of DNA methylation patterns that is characterized by a reduced dynamic range and increased heterogeneity of global methylation patterns. These changes in methylation variability were accompanied by a reduced connectivity of transcriptional networks. Our findings thus define the loss of epigenetic regulatory fidelity as a key feature of the aging epigenome.