Holly Alice C, Pilling Luke C, Hernandez Dena, Lee Benjamin P, Singleton Andrew, Ferrucci Luigi, Melzer David, Harries Lorna W
Institute of Biomedical and Clinical Sciences, University of Exeter Medical School, University of Exeter, Exeter EX2 5DW, UK.
Epidemiology and Public Health, University of Exeter Medical School, University of Exeter, Exeter EX1 2LU, UK.
Mech Ageing Dev. 2014 Jan;135:50-6. doi: 10.1016/j.mad.2014.01.005. Epub 2014 Jan 23.
Ageing in man is associated with changes to the splicing factor pool. A proportion of splicing factors are regulated during ageing by mechanisms involving the Ataxia Telangiectasia Mutated (ATM) gene, but the factors that determine the remaining proportion have yet to be identified. DNA methylation is known to be an important regulatory mechanism of gene expression. We assessed age-associated methylation and expression levels for 27 splicing factor genes, in peripheral blood samples from the InCHIANTI study. Examination of splicing patterns at specific loci was examined in a second cohort, the Exeter 10000 study. 27/502 methylation probes in 17 different genes were associated with age. Most changes were not associated with transcript expression levels or splicing patterns, but hypomethylation of the SF3B1 promoter region was found to mediate 53% of the relationship between age and transcript expression at this locus (p=0.02). DNA methylation does not appear to play a major role in regulation of the splicing factors, but changes in SF3B1 expression may be attributable to promoter hypomethylation at this locus. SF3B1 encodes a critical component of the U2 snRNP; altered expression of this gene may therefore contribute to the loss of regulated mRNA splicing that occurs with age.
人类衰老与剪接因子库的变化有关。一部分剪接因子在衰老过程中通过涉及共济失调毛细血管扩张突变（ATM）基因的机制受到调控，但决定其余部分的因素尚未确定。已知DNA甲基化是基因表达的重要调控机制。我们在InCHIANTI研究的外周血样本中评估了27个剪接因子基因的年龄相关甲基化和表达水平。在第二个队列Exeter 10000研究中检查了特定基因座的剪接模式。17个不同基因中的27/502个甲基化探针与年龄相关。大多数变化与转录本表达水平或剪接模式无关，但发现SF3B1启动子区域的低甲基化介导了该基因座年龄与转录本表达之间53%的关系（p=0.02）。DNA甲基化似乎在剪接因子的调控中不发挥主要作用，但SF3B1表达的变化可能归因于该基因座的启动子低甲基化。SF3B1编码U2 snRNP的关键成分；因此，该基因表达的改变可能导致随着年龄增长出现的mRNA剪接调控丧失。
