Regulation of the circadian clock inC. elegansby clock gene homologskin-20andlin-42

Abstract

Circadian rhythms are endogenous oscillations present in nearly all organisms from prokaryotes to humans, allowing them to adapt to cyclical environments close to 24 hours. Circadian rhythms are regulated by a central clock, which is based on a transcription-translation feedback loop. One important protein in the central loop in metazoan clocks is PERIOD, which is regulated in part by Casein kinase 1ε/δ (CK1ε/δ) phosphorylation. In the nematodeCaenorhabditis elegans,periodandcasein kinase 1ε/δare conserved aslin-42andkin-20, respectively. Here we studied the involvement oflin-42andkin-20in circadian rhythms of the adult nematode using a bioluminescence-based circadian transcriptional reporter. We show that mutations oflin-42andkin-20generate a significantly longer endogenous period, suggesting a role for both genes in the nematode circadian clock, as in other organisms. These phenotypes can be partially rescued by overexpression of either gene under their native promoter. Both proteins are expressed in neurons and seam cells, a population of epidermal stem cells inC. elegansthat undergo multiple divisions during development. Depletion of LIN-42 and KIN-20 specifically in neuronal cells after development was sufficient to lengthen the period of oscillatingsur-5expression. Therefore, we conclude that LIN-42 and KIN-20 are critical regulators of the adult nematode circadian clock through neuronal cells.

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

“…The pdfr-1 gene, which was highly autocorrelated in our data, showed no consistent expression between datasets. 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.…”

“…To investigate circadian gene expression rhythms in C. elegans, we used combined 12:12-hour cycles of light and temperature to synchronise (entrain) nematodes (light at 20°C: dark at 15°C). Our rationale for using these dual environmental inputs was that C. elegans is sensitive to both light [49,50] and temperature [64,65] and both sensory inputs have previously been reported to function as entrainment cues (zeitgebers; 'time givers') for gene expression rhythms in C. elegans [14][15][16]29,66]. While temperature has been used to entrain rhythms in other more established poikilothermic models, light is the better studied and reportedly more effective zeitgeber [1,11,[67][68][69][70][71].…”

A conserved chronobiological complex timesC. elegansdevelopment

“…mouse PER2 at 1225 amino acids (Jeon et al , 1999). LIN-42 lacks a CRY-binding domain, consistent with a lack of CRY orthologue in C. elegans , and in its tandem PER-ARNT-SIM (PAS) domains, only PAS-B is well conserved, adopts a canonical fold, and mediates dimerization in a mode identical to mammalian PER (Lamberti et al , 2023; Migliori et al , 2023). Finally, two stretches of sequence, previously termed SYQ and LT according to their first amino acids (Tennessen et al , 2006), bear sequence homology to the two PER CK1BD subdomains, CK1BD-A and CK1BD-B, but their function has remained unexplored.…”

“…The weak phenotypes seen with our precise deletion are particularly striking when considering that the PAS domains, and specifically the highly conserved PAS-B domain, mediate LIN-42 dimerization (Lamberti et al , 2023) - a function that is important for PER activity in circadian rhythms (Zheng et al , 1999). Although it remains to be determined whether the PAS domains are necessary for LIN-42 dimerization in vivo , it seems possible that LIN-42’s molting timing function does not require dimerization.…”

Circadian clock disruption engages the DREAM complex in suppressing cellular health

“…In C. elegans, we employed RNAi-mediated gene inactivation to knock down a core component of the circadian clock PER/ lin-42 6–10 . The complete loss of lin-42 function was previously found to cause accelerated aging and early death in the nematodes 11 .…”