Effects of aging on circadian patterns of gene expression in the human prefrontal cortex
Effects of aging on circadian patterns of gene expression in the human prefrontal cortex
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DOI：
10.1073/pnas.1508249112
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发表时间：
2016-01-05
影响因子：
11.1
通讯作者：
McClung, Colleen A.
中科院分区：
文献类型：
--
作者：
Chen, Cho-Yi;Logan, Ryan W.;McClung, Colleen A.
随着年龄的增长，昼夜节律会发生显着变化，包括向“早晨”时钟型转变以及循环激素节律性的丧失。然而，衰老对人脑分子节律的影响仍然难以捉摸。在这里，我们使用先前描述的死亡时间分析来识别整个基因组中在人类前额叶皮层 [布罗德曼区 11 (BA11) 和 BA47] 中表达具有显着昼夜节律的转录本。通过微阵列分析测定 146 个个体的表达水平。在检测到的转录本中发现了相似的表达节律性（P < 0.05）。通过对两个大脑区域的荟萃分析，我们确定了一组具有显着昼夜节律表达的 235 个核心基因 (q < 0.05)。这 235 个基因在两个区域之间的表达阶段显示出 92% 的一致性。除了典型的核心昼夜节律基因之外，还发现许多其他基因在大脑中表现出节律性表达。值得注意的是，我们鉴定了超过 1,000 个基因（BA11 中 1,186 个；BA47 中 1,591 个）表现出年龄依赖性节律或节律模式随衰老而改变。有趣的是，一组转录本在老年人中获得了节律性，这可能代表了由于规范时钟功能丧失而产生的补偿机制。因此，我们证实可以可靠地测量人脑中的节律基因表达，并首次（据我们所知）识别出分子节律随衰老而发生的显着变化，这可能会导致晚年认知、睡眠和情绪的改变。
With aging, significant changes in circadian rhythms occur, including a shift in phase toward a "morning" chronotype and a loss of rhythmicity in circulating hormones. However, the effects of aging on molecular rhythms in the human brain have remained elusive. Here, we used a previously described time-of-death analysis to identify transcripts throughout the genome that have a significant circadian rhythm in expression in the human prefrontal cortex [Brodmann's area 11 (BA11) and BA47]. Expression levels were determined by microarray analysis in 146 individuals. Rhythmicity in expression was found in similar to 10% of detected transcripts (P < 0.05). Using a metaanalysis across the two brain areas, we identified a core set of 235 genes (q < 0.05) with significant circadian rhythms of expression. These 235 genes showed 92% concordance in the phase of expression between the two areas. In addition to the canonical core circadian genes, a number of other genes were found to exhibit rhythmic expression in the brain. Notably, we identified more than 1,000 genes (1,186 in BA11; 1,591 in BA47) that exhibited age-dependent rhythmicity or alterations in rhythmicity patterns with aging. Interestingly, a set of transcripts gained rhythmicity in older individuals, which may represent a compensatory mechanism due to a loss of canonical clock function. Thus, we confirm that rhythmic gene expression can be reliably measured in human brain and identified for the first time (to our knowledge) significant changes in molecular rhythms with aging that may contribute to altered cognition, sleep, and mood in later life.