CYCLOPS reveals human transcriptional rhythms in health and disease

Abstract

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.gene expression | biological rhythms | machine learning | autoencoder | circadian rhythms C ircadian rhythms are nearly ubiquitous in nature. In animals, much of physiology and behavior is under circadian control. Body temperature, hormonal rhythms, blood pressure, and locomotor activity are just a few of the processes displaying daily rhythms. In circadian model systems (e.g., cyanobacteria, Neurospora, Arabidopsis, Drosophila, and mice), high-resolution time sampling is straightforward, and experiments show that a substantial fraction of the transcriptome is under clock control. For example, in mice, a majority of genes are clock regulated in at least 1 of 12 different organs (1).Circadian rhythms are also critical for humans. Shift work-induced circadian misalignment is associated with higher rates of metabolic, cardiovascular, and neoplastic disease. Clinical experience suggests time of day can have a marked effect on disease severity (2-4). Indeed, the majority of the best-selling prescription drugs and World Health Organization essential medicines target molecules that oscillate in mice (1). However, translation of these findings to clinical medicine remains slow. How does human molecular physiology change with circadian time? In mice, and presumably humans, circadian output genes are markedly different in each tissue. Obviously, repeated sampling from most human organs is not possible. As a result, we have limited ability to study human molecular rhythms and relate them to either normal or disease physiology.One approach is to analyze temporally ...

CRY1-CBS binding regulates circadian clock function and metabolism

“…S1K, L) [22,25,26]. Reconstructed human lung and liver rhythms similarly show oscillations in CBS expression [27]. Time course microarray studies demonstrate that Cbs expression is reduced in Clock mutant animals and altered circadian rhythmicity ( Fig.…”

TimeTeller: a New Tool for Precision Circadian Medicine and Cancer Prognosis

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What’s next for chronobiology and drug discovery

“…Most clinical samples are collected at time of visit or post-mortem in the extreme case, and the specific time of collection is not always on record. In a recent study [25], a computational tool was reported to assign time series to unordered clinical samples, which revealed dysregulated, but not disrupted, rhythms in hepatocellular carcinoma. This approach can be applied to illuminate circadian rhythms of other clock-related diseases, advancing our understanding of circadian etiology and design of targeted choronomedine.…”