Research Article

Diurnal transcriptome atlas of a primate across major neural and peripheral tissues

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Science  16 Mar 2018:
Vol. 359, Issue 6381, eaao0318
DOI: 10.1126/science.aao0318

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Daily transcription cycling in the baboon

Much of our knowledge about the important effects of circadian rhythms in physiology comes from studies of mice, which are nocturnal. Mure et al. report transcriptional profiles from many tissues and brain regions in baboons over a 24-hour period (see the Perspective by Millius and Ueda). The results emphasize how extensive rhythmic expression is, with more than 80% of protein-coding genes involved. They also highlight unanticipated differences between the mouse and baboon in the cycling of transcripts in various tissues. The findings provide a comprehensive analysis of circadian variation in gene expression for a diurnal animal closely related to humans.

Science, this issue p. eaao0318; see also p. 1210

Structured Abstract

INTRODUCTION

The interaction among cell-autonomous circadian oscillators—daily cycles of activity–rest and feeding–fasting—produces diurnal rhythms in gene expression in almost all animal tissues. These rhythms control the timing of a wide range of functions across different organs and brain regions, affording optimal fitness. Chronic disruption of these rhythms predisposes to and are hallmarks of numerous diseases and affective disorders.

RATIONALE

Time-series gene expression studies in a limited number of tissues from rodents have shown that 10 to 40% of the genome exhibits a ~24-hour rhythm in expression in a tissue-specific manner. However, rhythmic expression data from diverse tissues and brain regions from humans or our closest primate relatives is rare. Such multitissue diurnal gene expression data are necessary for gaining mechanistic understanding of how spatiotemporal orchestration of gene expression maintains normal physiology and behavior. We used a RNA sequencing technique to assess gene expression in major tissues and brain regions from baboons (a primate closely related to humans) housed under a defined 24-hour light–dark and feeding–fasting schedule.

RESULTS

We assessed gene expression in 64 different tissues and brain regions of male baboons, collected every 2 hours over the 24-hour day. Tissue-specific transcriptomes in baboon were comparable with that from humans (Human GTEx data set). We detected >25,000 expressed transcripts, including protein-coding and -noncoding RNAs. Nearly 11,000 genes were commonly expressed in all tissues. These universally expressed genes (UEGs) encoded for basic cellular functions such as transcription, RNA processing, DNA repair, protein homeostasis, and cellular metabolism. The remainders were expressed in distinct sets of tissues, with ~1500 genes expressed exclusively in a single tissue.

Rhythmic transcripts were found in all tissues, but the number of cycling transcripts varied from ~200 to >3000 in a given tissue, with only limited overlap in the repertoire of rhythmic transcripts between tissues. Of the 11,000 UEGs, the vast majority (96.6%) showed 24-hour rhythmicity in at least one tissue. A majority (>80%) of the 18,000 protein-coding genes detected also exhibited 24-hour rhythms in expression. The most enriched rhythmic transcripts across tissues were core clock components and their immediate output targets. However, their relative abundance and robustness of daily rhythms varied across tissues. Considered at the organismal level, global rhythmic transcription in 64 tissues organized into bursts of peak transcription, during early morning and late afternoon (when 11,000 transcripts reach their peak level). By contrast, during a relative “quiescent phase” in early evening that coincides with the onset of sleep and no food intake, only 700 rhythmic transcripts reach their peak expression level.

CONCLUSION

The daily expression rhythms in >80% of protein-coding genes, encoding diverse biochemical and cellular functions, constitutes by far the largest regulatory mechanism that integrates diverse biochemical functions within and across cell types. From a translational point of view, rhythmicity may have a major impact in health because 82.2% of genes coding for proteins that are identified as druggable targets by the U.S. Food and Drug Administration show cyclic changes in transcription.

Spatiotemporal gene expression atlas of a primate.

(Left) Gene expression analysis across 64 tissues of a diurnal primate sampled over the 24-hour day shows that 82% of protein-coding genes are rhythmic in at least one tissue. (Right) Rhythmic expression is tissue-specific and confers an additional layer of regulation and identity to the transcriptome of a given tissue.

Abstract

Diurnal gene expression patterns underlie time-of-the-day–specific functional specialization of tissues. However, available circadian gene expression atlases of a few organs are largely from nocturnal vertebrates. We report the diurnal transcriptome of 64 tissues, including 22 brain regions, sampled every 2 hours over 24 hours, from the primate Papio anubis (baboon). Genomic transcription was highly rhythmic, with up to 81.7% of protein-coding genes showing daily rhythms in expression. In addition to tissue-specific gene expression, the rhythmic transcriptome imparts another layer of functional specialization. Most ubiquitously expressed genes that participate in essential cellular functions exhibit rhythmic expression in a tissue-specific manner. The peak phases of rhythmic gene expression clustered around dawn and dusk, with a “quiescent period” during early night. Our findings also unveil a different temporal organization of central and peripheral tissues between diurnal and nocturnal animals.

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