Clin Epigenetics. 2011 Aug;2(2):349-60. doi: 10.1007/s13148-011-0042-6. Epub 2011 Jun 12.
DNA methylation plays an integral role in development and aging through epigenetic regulation of genome function. DNA methyltransferase 1 (Dnmt1) is the most prevalent DNA methyltransferase that maintains genomic methylation stability. To further elucidate the function of Dnmt1 in aging and age-related diseases, we exploited the Dnmt1+/- mouse model to investigate how Dnmt1 haploinsufficiency impacts the aging process by assessing the changes of several major aging phenotypes. We confirmed that Dnmt1 haploinsufficiency indeed decreases DNA methylation as a result of reduced Dnmt1 expression. To assess the effect of Dnmt1 haploinsufficiency on general body composition, we performed dual-energy X-ray absorptiometry analysis and showed that reduced Dnmt1 activity decreased bone mineral density and body weight, but with no significant impact on mortality or body fat content. Using behavioral tests, we demonstrated that Dnmt1 haploinsufficiency impairs learning and memory functions in an age-dependent manner. Taken together, our findings point to the interesting likelihood that reduced genomic methylation activity adversely affects the healthy aging process without altering survival and mortality. Our studies demonstrated that cognitive functions of the central nervous system are modulated by Dnmt1 activity and genomic methylation, highlighting the significance of the original epigenetic hypothesis underlying memory coding and function.
DNA 甲基化通过对基因组功能的表观遗传调控，在发育和衰老中发挥着重要作用。DNA 甲基转移酶 1（Dnmt1）是最常见的 DNA 甲基转移酶，它维持基因组甲基化的稳定性。为了进一步阐明 Dnmt1 在衰老和与年龄相关的疾病中的功能，我们利用 Dnmt1+/- 小鼠模型来研究 Dnmt1 杂合不足如何通过评估几种主要衰老表型的变化来影响衰老过程。我们证实 Dnmt1 杂合不足确实会由于 Dnmt1 表达减少而导致 DNA 甲基化减少。为了评估 Dnmt1 杂合不足对全身成分的影响，我们进行了双能 X 射线吸收法分析，结果表明 Dnmt1 活性降低会降低骨矿物质密度和体重，但对死亡率或体脂肪含量没有显著影响。通过行为测试，我们证明 Dnmt1 杂合不足以年龄依赖的方式损害学习和记忆功能。总之，我们的研究结果表明，降低基因组甲基化活性可能会对健康的衰老过程产生不利影响，而不会改变生存和死亡率。我们的研究表明，中枢神经系统的认知功能受 Dnmt1 活性和基因组甲基化的调节，突出了记忆编码和功能背后原始表观遗传假说的重要性。
