Day-night and seasonal variation of human gene expression across tissues

  1. Valentin Wucher
  2. Reza Sodaei
  3. Raziel Amador
  4. Manuel Irimia
  5. Roderic Guigó

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Abstract

Circadian and circannual cycles trigger physiological changes whose reflection on human transcriptomes remains largely uncharted. We used the time and season of death of 932 individuals from GTEx to jointly investigate transcriptomic changes associated with those cycles across multiple tissues. Overall, most variation across tissues during day-night and among seasons was unique to each cycle. Although all tissues remodeled their transcriptomes, brain and gonadal tissues exhibited the highest seasonality, whereas those in the thoracic cavity showed stronger day-night regulation. Core clock genes displayed marked day-night differences across multiple tissues, which were largely conserved in baboon and mouse, but adapted to their nocturnal or diurnal habits. Seasonal variation of expression affected multiple pathways, and it was enriched among genes associated with the immune response, consistent with the seasonality of viral infections. Furthermore, they unveiled cytoarchitectural changes in brain regions. Altogether, our results provide the first combined atlas of how transcriptomes from human tissues adapt to major cycling environmental conditions. This atlas may have multiple applications; for example, drug targets with day-night or seasonal variation in gene expression may benefit from temporally adjusted doses.

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  1. Version published to 10.1371/journal.pbio.3001986
  2. Version published to 10.1101/2021.02.28.433266v2 on bioRxiv
  3. ScreenIT

    SciScore for 10.1101/2021.02.28.433266: (What is this?)

    Please note, not all rigor criteria are appropriate for all manuscripts.

    Table 1: Rigor

    NIH rigor criteria are not applicable to paper type.

    Table 2: Resources

    Software and Algorithms
    SentencesResources
    GENCODE v26 (73) was used for GTEx as well as the annotation for the protein-coding genes.
    GENCODE
    suggested: (GENCODE, RRID:SCR_014966)
    The analyses were run using R v3.6.1 (74), the voom-limma pipeline (19, 75) and the TMM normalisation method from edgeR (76, 77).
    edgeR
    suggested: (edgeR, RRID:SCR_012802)
    Then, we used the enrichment analysis tool Enrichr (78, 79) and we selected the ten Wikipathway and/or GO functional terms with the highest combined score.
    Enrichr
    suggested: (Enrichr, RRID:SCR_001575)
    The correspondence between the Ensembl protein ID and the UniProtKB ID with the Ensembl gene ID was downloaded using BioMart from Ensembl (80).
    UniProtKB
    suggested: (UniProtKB, RRID:SCR_004426)
    Ensembl
    suggested: (Ensembl, RRID:SCR_002344)
    The Ensembl peptide IDs were linked to their respective Ensembl gene ID using R and the biomaRt package (81, 82).
    biomaRt
    suggested: (biomaRt, RRID:SCR_019214)
    The gene IDs for hormones with deprecated peptide IDs were retrieved manually using the Ensembl website (http://www.ensembl.org) and the ones that were obscelets were removed.
    http://www.ensembl.org
    suggested: (Homologous Sequences in Ensembl Animal Genomes, RRID:SCR_008356)

    Results from OddPub: Thank you for sharing your data.

    Results from LimitationRecognizer: We detected the following sentences addressing limitations in the study:
    We have addressed this limitation by discretizing the continuous circadian variation into day vs. night, and the circannual variation into seasons. In addition, because the time of the day without knowledge of the actual day of the year and the geographical location in which death occurred does not fully inform whether death occurred under daylight, we excluded the data from donors that died within time intervals when the presence of daylight could not be confidently determined (twilight zone). Therefore, we do not refer to the variations reported here as circadian and circannual, but as day-night and seasonal, respectively. Despite these caveats, our approach was able to properly capture at least part of the real circadian and circannual transcriptional variation, since we have been able to recapitulate previous findings regarding day-night variation. We found that the effect of day-night variation in gene expression was comparable to that of the seasonal cycle, but affecting very different genes and tissues. Day-night variation in gene expression was more prominent in liver, lung, heart, and upper digestive tract, reflecting the involvement of the organs of the thoracic cavity in circadian processes (65), while seasonal variation had the strongest effect in brain subregions and testis, mirroring the role of the brain-gonadal hormonal axis in regulating the physiological responses to seasonal variation (66). Moreover, we showed that the effect of day-night and/or seasonal va...

    Results from TrialIdentifier: No clinical trial numbers were referenced.

    Results from Barzooka: We did not find any issues relating to the usage of bar graphs.

    Results from JetFighter: We did not find any issues relating to colormaps.

    Results from rtransparent:
    • Thank you for including a conflict of interest statement. Authors are encouraged to include this statement when submitting to a journal.
    • Thank you for including a funding statement. Authors are encouraged to include this statement when submitting to a journal.
    • No protocol registration statement was detected.

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  4. Version published to 10.1101/2021.02.28.433266v1 on bioRxiv