A circadian gene expression atlas in mammals: Implications for biology and medicine
A circadian gene expression atlas in mammals: Implications for biology and medicine
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DOI：
10.1073/pnas.1408886111
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发表时间：
2014-11-11
影响因子：
11.1
通讯作者：
Hogenesch, John B.
中科院分区：
文献类型：
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作者：
Zhang, Ray;Lahens, Nicholas F.;Hogenesch, John B.
为了表征生物钟在小鼠生理和行为中的作用，我们使用RNA-seq和DNA阵列来定量12个小鼠器官随时间的转录组。我们发现43%的蛋白质编码基因在体内某个地方的转录中表现出昼夜节律，主要是以器官特异性的方式。在大多数器官中，我们注意到许多振荡基因的表达在黎明和黄昏前的转录“高峰时间”达到峰值。通过观察节律基因的基因组图谱，我们发现它们聚集在一起，比非振荡基因更长，剪接形式也更多。系统水平的分析揭示了整个身体基因通路的复杂节奏编排。我们还发现了1,000多种已知和新型非编码RNA（ncRNA）的表达振荡。支持其在介导时钟功能中的潜在作用，小鼠和人类之间保守的ncRNA显示出与蛋白质编码基因相似比例的节律性表达。重要的是，我们还发现，大多数畅销药物和世界卫生组织基本药物直接针对节律基因的产物。这些药物中的许多具有短半衰期，并且可能受益于定时剂量。总之，这项研究强调了哺乳动物生物钟的关键，系统和令人惊讶的作用，并为时间疗法的发展提供了蓝图。
To characterize the role of the circadian clock in mouse physiology and behavior, we used RNA-seq and DNA arrays to quantify the transcriptomes of 12 mouse organs over time. We found 43% of all protein coding genes showed circadian rhythms in transcription somewhere in the body, largely in an organ-specific manner. In most organs, we noticed the expression of many oscillating genes peaked during transcriptional "rush hours" preceding dawn and dusk. Looking at the genomic landscape of rhythmic genes, we saw that they clustered together, were longer, and had more splice-forms than nonoscillating genes. Systems-level analysis revealed intricate rhythmic orchestration of gene pathways throughout the body. We also found oscillations in the expression of more than 1,000 known and novel noncoding RNAs (ncRNAs). Supporting their potential role in mediating clock function, ncRNAs conserved between mouse and human showed rhythmic expression in similar proportions as protein coding genes. Importantly, we also found that the majority of best-selling drugs and World Health Organization essential medicines directly target the products of rhythmic genes. Many of these drugs have short half-lives and may benefit from timed dosage. In sum, this study highlights critical, systemic, and surprising roles of the mammalian circadian clock and provides a blueprint for advancement in chronotherapy.