bims-ciryme 2025-09-07 papers

iScience. 2025 Sep 19. 28(9): 113292

A novel circadian behavior rhythm in arrhythmic Period triple knockout mice revealed by constant light exposure.

S K Tahajjul Taufique, Alexandra J Brown, Srinidhi Mahadevan, David E Ehichioya, Sofia Farah, Melody Shen, Shin Yamazaki.

The current model for autonomous circadian oscillation is based on the transcriptional-translational feedback loops of circadian genes. The deletion of one of the circadian genes and its paralogs leads to arrhythmicity. Period 1/2/3 triple knockout (Per KO) mice exhibit arrhythmic behavior in constant darkness. Molecular oscillations in the primary pacemaker in the suprachiasmatic nucleus (SCN) and peripheral oscillators are blunted in these mice. Here we report that a simple environmental manipulation, constant light exposure (LL), revealed a ∼22 h behavior rhythm in Per KO mice. Ex vivo SCN explanted from behaviorally rhythmic Per KO mice showed disrupted calcium rhythms, suggesting that the rescued rhythm is likely independent of the SCN. Although the mechanism by which LL reveals residual circadian rhythm in Per KO mice remains to be discovered, this unexpected novel effect of LL is greatly contrary to the well-documented disruptive effect of LL on the SCN clock in wildtype rodents.

Keywords: Biological sciences; Molecular neuroscience; Neuroscience

DOI: https://doi.org/10.1016/j.isci.2025.113292

Sci Rep. 2025 Aug 31. 15(1): 32010

Circadian rhythms in pediatric high-grade gliomas may contribute to treatment efficacy.

Ella A Nettnin, Cesar A Garcia, Fudhial F Sayed, Ethan Schonfeld, Thien Nguyen, Maria Isabel Barros Guinle, Claudia K Petritsch, Erin M Gibson, Laura M Prolo.

Pediatric high-grade gliomas (pHGG) are highly invasive with poor survival outcomes. Timing of Temozolomide administration has been shown to affect survival of adult patients with glioblastoma. We investigated whether pHGGs express circadian genes rhythmically and whether underlying rhythms affect Temozolomide sensitivity. Circadian gene expression in pediatric gliomas was analyzed using PedcBioPortal. Immunoblotting was used to assess protein levels in patient-derived pHGG lines and in high- and low- grade (pLGG) glioma specimens. Rhythmic gene expression in pHGG lines was measured via qPCR, and Temozolomide efficacy was tested during peak versus trough Bmal1 expression. Patient data revealed significantly different mRNA expression in multiple circadian genes between pHGGs and pLGGs, including higher Bmal1 expression in pHGG specimens and lower Rev-Erbα expression. Significantly higher BMAL1 and CLOCK protein levels and lower REV-ERBα were present in pHGG versus pLGG tissue specimens. Our three pHGG lines displayed rhythmic Bmal1 and Rev-Erbα expression post-synchronization. We found significantly decreased proliferation when Temozolomide was applied during trough versus peak Bmal1 expression. The positive arm of the circadian clock appears upregulated in pHGGs compared to pLGGs. Pediatric HGGs rhythmically express circadian genes and exhibit differential Temozolomide sensitivity based on timing of administration.

Keywords: Chronotherapy; Circadian medicine; Circadian rhythms; Pediatric glioblastoma; Pediatric high-grade glioma; Pediatric low-grade glioma

DOI: https://doi.org/10.1038/s41598-025-17461-9

Proc Natl Acad Sci U S A. 2025 Sep 09. 122(36): e2517648122

Daily liver rhythms: Coupling morphological and molecular oscillations.

Ueli Schibler, Flore Sinturel, Felix Naef, Alan Gerber, David Gatfield.

In mammals, a hierarchically organized circadian timing system orchestrates daily rhythms of nearly all physiology. A master pacemaker in the brain's suprachiasmatic nucleus (SCN) synchronizes subsidiary clocks in most peripheral organs. By driving anabolic and catabolic cycles of proteins, lipids, and carbohydrates and by detoxifying endo- and xenobiotic components, the liver plays an important role in adapting the metabolic needs to rest-activity rhythms. In keeping with these functions, the liver expresses many clock-controlled genes that are required for these processes. Remarkably, however, this organ also fluctuates in size and morphological parameters. In mice, the mass of the liver increases and decreases by 30 to 40% during the 24-h day. The oscillation in liver mass is accompanied by daily rhythms of similar amplitudes in hepatocyte cell size and global RNA and protein accumulation. The number of ribosomes, which parallels the ups and downs of liver size, appears to be the rate-limiting factor in driving the diurnal rhythms of overall protein synthesis. Obviously, the rapid increase in hepatocyte size within the liver engenders mechanical stress, which must be dealt with by increasing the physical robustness of cells. Indeed, the actin cytoskeleton of hepatocytes undergoes dramatic polymerization cycles. Thus, massive intracellular and subcortical F-actin bundles are assembled during the night, at which the liver reaches its maximal size. In turn, the oscillation in actin polymerization elicits rhythms in myocardin-related transcription factors-serum response factor signaling, which participate in the circadian transcription of the core clock gene Per2 and thereby contribute to the synchronization of hepatocyte clocks.

Keywords: actin cytoskeleton; diurnal; liver size; ribosome assembly; synchronization

DOI: https://doi.org/10.1073/pnas.2517648122

Proc Natl Acad Sci U S A. 2025 Sep 09. 122(36): e2506928122

Mutations in the circadian cycle drive adaptive plasticity in cyanobacteria.

Alfonso Mendaña, María Santos-Merino, Raquel Gutiérrez-Lanza, Marina Domínguez-Quintero, Juan Manuel Medina-Méndez, Ana González-Guerra, Víctor Campa, Miguel Baez, Magaly Ducos-Galand, Rocío López-Igual, Daniel C Volke, Muriel Gugger, Pablo I Nikel, Didier Mazel, Fernando de la Cruz, Raúl Fernández-López.

Circadian clocks allow organisms to anticipate daily fluctuations in light and temperature, but how this anticipatory role promotes adaptation to different environments remains poorly understood. Here, we subjected the cyanobacterium Synechococcus elongatus PCC 7942 to a long-term evolution experiment under high light, high temperature, and elevated CO2 levels. After 1,200 generations, we obtained a strain exhibiting a 600% increase in growth rate. Whole-genome sequencing revealed three mutations fixed in the evolved population, two of which were sufficient to recapitulate the fast-growing phenotype in the wild type. A mutation in the promoter of the shikimate kinase aroK led to its overexpression, while a mutation in the central circadian regulator sasA disrupted both the phase and amplitude of the circadian rhythm. Changes in circadian control led to widespread perturbations in the transcriptome and metabolome. These included major shifts in the Calvin-Benson-Bassham cycle and glycogen storage dynamics. While these changes increased fitness under the experimental conditions, they caused maladaptation when light or CO2 levels were altered, revealing a trade-off between fitness and environmental flexibility. Our results demonstrate that mutations in circadian control can drive fast adaptation by modulating central metabolism, underscoring the circadian cycle as a cornerstone of cellular plasticity. Thus, targeting the circadian cycle could be key to engineering cyanobacterial strains optimized for carbon fixation and biomass production.

Keywords: Cyanobacteria; circadian rhythm; experimental evolution

DOI: https://doi.org/10.1073/pnas.2506928122