CYCLOPS reveals human transcriptional rhythms in health and disease
CYCLOPS reveals human transcriptional rhythms in health and disease
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DOI：
10.1073/pnas.1619320114
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发表时间：
2017-05-16
影响因子：
11.1
通讯作者：
Kim, Junhyong
中科院分区：
文献类型：
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作者：
Anafi, Ron C.;Francey, Lauren J.;Kim, Junhyong
昼夜节律调节生理学的许多方面。在过去的20年里，对这些节奏的分子基础的了解已经爆炸了。然而，这些数据大多来自模式生物，转化为临床实践是有限的。在这里，我们提出了一种方法，以确定人类的分子节奏从成千上万的无序表达测量。我们的算法，周期结构循环排序（CYCLOPS），使用进化守恒和机器学习来识别高维数据中的椭圆结构。根据这个结构，CYCLOPS估计每个样本的相位。我们使用时序小鼠和人类数据验证了CYCLOPS，并证明了其在两个独立研究中心的人类数据上的一致性。我们使用这种方法来识别人类肝脏和肺部的节律性转录物，包括数百个药物靶点和疾病基因。重要的是，对于许多基因，表达的昼夜变化超过了遗传和其他环境因素的变化。我们还分析了肝细胞癌样本，并显示这些实体瘤保持昼夜节律功能，但具有异常输出。最后，为了展示这种方法如何催化医学翻译，我们展示了给药时间可以暂时将化疗药物链脲佐菌素的剂量限制性毒性与疗效分离。总之，这些数据显示了CYCLOPS和时间重建在基础昼夜节律研究和临床医学中的作用。
Circadian rhythms modulate many aspects of physiology. Knowledge of the molecular basis of these rhythms has exploded in the last 20 years. However, most of these data are from model organisms, and translation to clinical practice has been limited. Here, we present an approach to identify molecular rhythms in humans from thousands of unordered expression measurements. Our algorithm, cyclic ordering by periodic structure (CYCLOPS), uses evolutionary conservation and machine learning to identify elliptical structure in high-dimensional data. From this structure, CYCLOPS estimates the phase of each sample. We validated CYCLOPS using temporally ordered mouse and human data and demonstrated its consistency on human data from two independent research sites. We used this approach to identify rhythmic transcripts in human liver and lung, including hundreds of drug targets and disease genes. Importantly, for many genes, the circadian variation in expression exceeded variation from genetic and other environmental factors. We also analyzed hepatocellular carcinoma samples and show these solid tumors maintain circadian function but with aberrant output. Finally, to show how this method can catalyze medical translation, we show that dosage time can temporally segregate efficacy from dose-limiting toxicity of streptozocin, a chemotherapeutic drug. In sum, these data show the power of CYCLOPS and temporal reconstruction in bridging basic circadian research and clinical medicine.