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A database of tissue-specific rhythmically expressed human genes has potential applications in circadian medicine

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Science Translational Medicine  12 Sep 2018:
Vol. 10, Issue 458, eaat8806
DOI: 10.1126/scitranslmed.aat8806
  • Fig. 1 Population-level rhythms in gene expression across human anatomy.

    (A) Number of genes that met criteria for rhythmicity (FDR < 0.05; rAmp ≥ 0.1; R2 ≥ 0.1) in at least 1 of the 13 tissues. Periodic analysis was performed by cosinor regression on expression values for 160 CYCLOPS-ordered samples per tissue, as discussed in fig. S1 and Materials and Methods. See fig. S2 for numbers of rhythmic genes discovered at varying FDR thresholds. (B) Set of 54 ubiquitous genes cycling in at least 8 of 13 human tissues, grouped by prior circadian context as reported in CircaDB (darkest blue, homolog cycles in 16 of 16 mouse tissues; lightest blue, not cycling in any of the 16 mouse tissues). (C) Average acrophases of core clock genes (external circle) across all human tissues compared to mouse [internal circle, average across 12 tissues reported by Zhang et al. (3)]. Average coefficient of determination (R2, a measure of cycling robustness) is indicated by point size, and phase variability (Phase var) is indicated by color. Peak phase of ARNTL (human) or Arntl (mouse) was set as 0 for comparison. (D) Average acrophases of all other (noncore clock) human ubiquitous cycling genes. Genes located more distant from the center have larger average amplitudes of oscillation (rAmp) across tissues where they cycle.

  • Fig. 2 Robust tissue-specific rhythms.

    (A) Distribution of robustness (R2, goodness of data fit to 24-hour sine wave) and (B) peak-to-trough ratio for all cyclers (gray) in each tissue; most clock genes (red) reside in the upper quartile in most tissues. (C) Distribution of acrophases for cyclers differs between tissue types. Light and dark shading represents inferred active and inactive phase based on Arntl expression, which is known to peak in anticipation of the inactive period in mammals. (D) UpSetR (18) to rank and visualize the intersection between multiple sets (tissues). Restricting input to the top 500 cyclers by FDR from each tissue, the largest intersections describe genes whose expression cycles only in a single tissue.

  • Fig. 3 Pharmacological links to molecular rhythms in the human population.

    (A) Of 7486 genes found to cycle in at least 1 of 13 human tissues sampled, 917 (12%) encode at least one drug target, transporter, or metabolizing enzyme (collectively referred to as “targets”). This represents a total of 2764 drug entities, both approved and experimental as logged in DrugBank (20), with targets that oscillate somewhere in the body. (B) Numbers of total (colored green) and pharmacologically active (colored blue) cycling drug targets by tissue type. (C) Cardiovascular-related tissues from ordered GTEx data. To enrich for high-amplitude cardio-cyclers, we limited to genes in the upper 50th percentile for rAmp within each tissue and FDR ≤0.1. Numbers of cardio-cyclers that meet these cycling criteria and are also drug targets are indicated in parentheses. (D) Cardio-cyclers targeted by select drug classes relevant to heart and vessel physiology. Plotted phase represents average peak phase across all cardiac tissues where that gene was found to cycle. (E) Expression values plotted as a function of sample phase for select cardio-cyclers. Coefficient of determination (R2) and peak-to-trough ratio (ptr) are indicated. Right: Genes that are also rhythmically expressed in whole mouse heart, with peak phases indicated by orange bars. ARNTL (human) or Arntl (mouse) was set to 0 for comparison.

  • Table 1 GTEx donor demographics.

    NA, not available.

    SexMaleFemale
    66%34%
    Age (years)20–2930–3940–4950–5960–6970–79
    8%7%17%34%32%3%
    DeathFastIntermediateSlowSudden-NaturalVentilatorNA
    4%5%10%26%53%1%

Supplementary Materials

  • www.sciencetranslationalmedicine.org/cgi/content/full/10/458/eaat8806/DC1

    Fig. S1. Pipeline for sample selection and CYCLOPS ordering for 13 tissues.

    Fig. S2. Numbers of cycling genes by different statistical thresholds and noncoding gene type.

    Fig. S3. Phase set enrichment in human and mouse counterpart tissues.

    Fig. S4. Gene expression traces for top cardio-cycling drug targets.

    Data file S1. Cosinor regression output for all genes and all tissues.

    Data file S2. Set of 54 genes that cycle in 8 or more of the 13 tissues.

    Data file S3. Set of 136 cardio-cycler drug targets.

  • The PDF file includes:

    • Fig. S1. Pipeline for sample selection and CYCLOPS ordering for 13 tissues.
    • Fig. S2. Numbers of cycling genes by different statistical thresholds and noncoding gene type.
    • Fig. S3. Phase set enrichment in human and mouse counterpart tissues.
    • Fig. S4. Gene expression traces for top cardio-cycling drug targets.
    • Legends for data files S1 to S3

    [Download PDF]

    Other Supplementary Material for this manuscript includes the following:

    • Data file S1 (Microsoft Excel format). Cosinor regression output for all genes and all tissues.
    • Data file S2 (Microsoft Excel format). Set of 54 genes that cycle in 8 or more of the 13 tissues.
    • Data file S3 (Microsoft Excel format). Set of 136 cardio-cycler drug targets.

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