Defining the age-dependent and tissue-specific circadian transcriptome in male mice

Cellular circadian clocks direct a daily transcriptional program that supports homeostasis. Emerging evidence supports age-associated changes in circadian functions. To define age-dependent changes at the systems level, we profiled the circadian transcriptome in the hypothalamus, lung, heart, kidney, skeletal muscle, and adrenal gland in 3 age groups. We found age-dependent and tissue-specific clock output changes. Aging reduced the number of rhythmically expressed genes (REGs), indicative of weakened circadian control. Many genes gained rhythmicity in old tissues, reflecting an adaptive response. REGs were enriched for the hallmarks of aging, adding a new dimension to understanding aging. Differential gene expression analysis found that there were temporally distinct clusters of genes in tissue-specific manner. This novel analysis extends the landscape of the understanding of aging. Increased daily gene expression variability is a common feature of aged tissues. Our data highlight the impact of aging on circadian function and temporal changes in gene expression. Overall design: Hypothalamus, lung, kidney, skeletal muscle, heart, and adrenal gland tissues from Young (6mo), Aged (18mo), and Old (27mo) male mice were collected every 4h for 48h to characterize the circadian transcriptome changes with age. Two samples per age were collected and pooled for RNAseq analysis.

细胞昼夜节律钟（cellular circadian clock）调控维持机体稳态的每日转录程序。日益增多的研究证据显示，昼夜节律功能会出现与年龄相关的改变。为从系统层面明确年龄依赖的节律变化，我们对3个年龄组小鼠的下丘脑、肺、心脏、肾脏、骨骼肌及肾上腺组织的昼夜节律转录组（circadian transcriptome）进行了全景分析。研究发现了兼具年龄依赖性与组织特异性的节律钟输出变化：衰老会减少节律表达基因（rhythmically expressed genes, REGs）的数量，提示昼夜节律调控作用减弱；而老年组织中大量基因重新获得节律性表达，则反映了一种适应性应答。节律表达基因显著富集于衰老特征相关通路，为衰老研究提供了全新维度。差异基因表达分析显示，不同组织中均存在具有时序特异性的基因簇。本项创新性分析拓展了人们对衰老机制的认知边界。每日基因表达变异程度升高是衰老组织的共同特征。本研究数据揭示了衰老对昼夜节律功能及基因表达时序变化的影响。实验设计概况：采集年轻（6月龄）、老龄（18月龄）、老年（27月龄）雄性小鼠的下丘脑、肺、肾脏、骨骼肌、心脏及肾上腺组织，每4小时采样1次，连续采集48小时，以解析衰老过程中的昼夜节律转录组变化。每个年龄组采集2份样本并混合，用于RNA测序（RNAseq）分析。