PDF(Pubmed)
Abstract：
DNA hydroxymethylation (5hmC), the most abundant oxidative derivative of DNA methylation, is typically enriched at enhancers and gene bodies of transcriptionally active and tissue-specific genes. Although aberrant genomic 5hmC has been implicated in age-related diseases, its functional role in aging remains unknown. Here, using mouse liver and cerebellum as model organs, we show that 5hmC accumulates in gene bodies associated with tissue-specific function and restricts the magnitude of gene expression changes with age. Mechanistically, 5hmC decreases the binding of splicing associated factors and correlates with age-related alternative splicing events. We found that various age-related contexts, such as prolonged quiescence and senescence, drive the accumulation of 5hmC with age. We provide evidence that this age-related transcriptionally restrictive function is conserved in mouse and human tissues. Our findings reveal that 5hmC regulates tissue-specific function and may play a role in longevity.
摘要：
DNA羟甲基化（5hmC），DNA甲基化的最丰富的氧化衍生物，通常在转录活性和组织特异性基因的增强子和基因体处富集。尽管异常基因组5hmC与年龄相关的疾病有关，它在衰老中的功能作用仍然未知。这里,以小鼠肝脏和小脑为模型器官，我们表明5hmC在与组织特异性功能相关的基因体中积累，并限制了基因表达随年龄变化的幅度。机械上,5hmC降低剪接相关因子的结合并与年龄相关的可变剪接事件相关。我们发现各种与年龄相关的背景，如长时间的静止和衰老，随着年龄的增长驱动5hmC的积累。我们提供的证据表明，这种年龄相关的转录限制性功能在小鼠和人类组织中是保守的。我们的发现表明，5hmC调节组织特异性功能，并可能在长寿中发挥作用。
