Evidence for conservation of primordial ∼12-hour ultradian gene programs in humans under free-living conditions

Abstract

While circadian rhythms are entrained to the once daily light-dark cycle of the sun, many marine organisms exhibit ~12h ultradian rhythms corresponding to the twice daily movement of the tides. Although human ancestors emerged from circatidal environment millions of years ago, direct evidence of the existence of ~12h ultradian rhythms in humans are lacking. Here, we performed prospective, temporal transcriptome profiling of peripheral white blood cells and identified robust ~12h transcriptional rhythms from three healthy subjects. Pathway analysis implicated ~12h rhythms effecting RNA and protein metabolism, with strong homology to the circatidal gene programs previously identified in Cnidarian marine species. We further observed ~12h rhythms of intron retention events of genes involved in MHC class I antigen presentation in all three subjects, synchronized to those of mRNA splicing gene expressions in each individual. Gene regulatory network inference revealed XBP1, GABPA and KLF7 as putative transcriptional regulators of human ~12h rhythms. These results thus establish human ~12h biological rhythms have a primordial evolutionary origin and are likely to have far-reaching implications in human health and disease.

The rhythmic transcriptional landscape inCaenorhabditis elegans: daily, circadian and novel 16-hour cycling gene expression revealed by RNA-sequencing

“…We also did not see concordant rhythmicity two previously described C. elegans circadian reporter genes: sur-5 [66,89], which showed no rhythm in any dataset, nor nlp-36 which was rhythmic in the 2010 study [14], and remained so in the reanalysed temperature-entrained data only. A final gene of interest, xbp-1, whose mammalian homologue has been associated with 12-hour ultradian expression rhythms [90][91][92][93], was rhythmic across all three datasets. This gene did show consistent expression in temperatureentrained and RNA-seq dataset, particularly during the entrainment phases (Figure S1).…”

“…Over 1000 genes (~7.5% of detected genes) were assigned to the Brown module, with many being well-represented by the eigengene expression profile. Ultradian (< 24-hour) rhythms have been widely reported in nature, including 12-hour harmonics of the circadian rhythm in mouse and human transcriptomic data [92,104] and also in C. elegans (again from the 2010 dataset) [93]. Circatidal rhythms, rhythms of a similar periodicity synchronised by tides, can also be seen in marine organisms across phyla, in some cases being contingent on expression of TTFL-essential genes and proteins [114][115][116][117][118][119].…”