Building and Mining an Atlas of the Mammalian Circadian Transcriptome

Nearly all mammals possess internal clocks that synchronize with the day-night cycles of their environments. These circadian clocks help temporally segregate competing or incompatible physiological processes to anticipated appropriate times of the day. As the mammalian clock system is principally regulated by transcription factors, numerous previous studies have sought to characterize gene-transcript oscillations as a primary means of gaining insight into what pathways are controlled by the clock. However, most studies have only examined one or two specific tissue types at a time, often with suboptimal sampling resolution. Little work has been done to analyze clock control at the organism level. Furthermore, despite the apparent importance of circadian rhythms in nearly all major physiological processes, actionable medical knowledge has been difficult to extract. This lack of translational insight is not due to a simple lack of data, but rather to gaps in assembling a big picture from scattered data and to deficiencies in analytical methods. The goal of this dissertation was to overcome these shortcomings by forging a comprehensive atlas of the mammalian circadian transcriptome. High-throughput techniques were used to identify circadian transcript rhythms at a high sampling resolution in twelve different organs. This work brought to light critical systemic roles of the mammalian circadian clock at the organism level, while providing a blueprint for future advancements in chronotherapy. Findings from this work have actionable implications for the dosing of many important drugs. An algorithm for analyzing gene-phase set enrichment was also developed to address insufficiencies in existing methods. Applying this algorithm to earlier data uncovered insights into the relative timing of circadian genes that were missed when using existing methods. Further mining of data from other labs revealed unexpected findings that challenge current paradigms in the field. Taken in sum, the work presented in this dissertation is an evaluation into how our internal clocks schedule the myriad aspects of our physiology on a daily basis, with striking ramifications for clinical medicine