bims-ciryme 2024-12-15 papers

Proc Natl Acad Sci U S A. 2024 Dec 17. 121(51): e2417678121

Genetic synchronization of the brain and liver molecular clocks defend against chrono-metabolic disease.

Lauren N Woodie, Ahren J Alberto, Brianna M Krusen, Lily C Melink, Mitchell A Lazar.

Nearly every cell of the body contains a circadian clock mechanism that is synchronized with the light-entrained clock in the suprachiasmatic nucleus (SCN). Desynchrony between the SCN and the external environment leads to metabolic dysfunction in shift workers. Similarly, mice with markedly shortened endogenous period due to the deletion of circadian REV-ERBα/β nuclear receptors in the SCN (SCN DKO) exhibit increased sensitivity to diet-induced obesity (DIO) on a 24 h light:dark cycle while mice with REV-ERBs deleted in hepatocytes (HepDKO) display exacerbated hepatosteatosis in response to a high-fat diet. Here, we show that inducing deletion of hepatocyte REV-ERBs in SCN DKO mice (Hep-SCN DDKO) rescued the exacerbated DIO and hepatic triglyceride accumulation, without affecting the shortened behavioral period. These findings suggest that metabolic disturbances due to environmental desynchrony with the central clock are due to effects on peripheral clocks which can be mitigated by matching peripheral and central clock periods even in a desynchronous environment. Thus, maintaining synchrony within an organism, rather than between endogenous and exogenous clocks, may be a viable target for the treatment of metabolic disorders associated with circadian disruption.

Keywords: REV-ERB; circadian rhythms; metabolism; obesity; suprachiasmatic Nucleus

DOI: https://doi.org/10.1073/pnas.2417678121

Plant Direct. 2024 Aug;8(8): e70001

Effects of light regimes on circadian gene co-expression networks in Arabidopsis thaliana.

Quentin Rivière, Virginie Raskin, Romário de Melo, Stéphanie Boutet, Massimiliano Corso, Matthieu Defrance, Alex A R Webb, Nathalie Verbruggen, Armand D Anoman.

Light/dark (LD) cycles are responsible for oscillations in gene expression, which modulate several aspects of plant physiology. Those oscillations can persist under constant conditions due to regulation by the circadian oscillator. The response of the transcriptome to light regimes is dynamic and allows plants to adapt rapidly to changing environmental conditions. We compared the transcriptome of Arabidopsis under LD and constant light (LL) for 3 days and identified different gene co-expression networks in the two light regimes. Our studies yielded unforeseen insights into circadian regulation. Intuitively, we anticipated that gene clusters regulated by the circadian oscillator would display oscillations under LD cycles. However, we found transcripts encoding components of the flavonoid metabolism pathway that were rhythmic in LL but not in LD. We also discovered that the expressions of many stress-related genes were significantly increased during the dark period in LD relative to the subjective night in LL, whereas the expression of these genes in the light period was similar. The nocturnal pattern of these stress-related gene expressions suggested a form of "skotoprotection." The transcriptomics data were made available in a web application named Cyclath, which we believe will be a useful tool to contribute to a better understanding of the impact of light regimes on plants.

Keywords: Arabidopsis thaliana; circadian rhythms; co‐expression networks; flavonoids; light regime; skotoprotection

DOI: https://doi.org/10.1002/pld3.70001

Proc Natl Acad Sci U S A. 2024 Dec 17. 121(51): e2412327121

Temperature-dependent fold-switching mechanism of the circadian clock protein KaiB.

Ning Zhang, Damini Sood, Spencer C Guo, Nanhao Chen, Adam Antoszewski, Tegan Marianchuk, Supratim Dey, Yunxian Xiao, Lu Hong, Xiangda Peng, Michael Baxa, Carrie Partch, Lee-Ping Wang, Tobin R Sosnick, Aaron R Dinner, Andy LiWang.

The oscillator of the cyanobacterial circadian clock relies on the ability of the KaiB protein to switch reversibly between a stable ground-state fold (gsKaiB) and an unstable fold-switched fold (fsKaiB). Rare fold-switching events by KaiB provide a critical delay in the negative feedback loop of this posttranslational oscillator. In this study, we experimentally and computationally investigate the temperature dependence of fold switching and its mechanism. We demonstrate that the stability of gsKaiB increases with temperature compared to fsKaiB and that the Q10 value for the gsKaiB → fsKaiB transition is nearly three times smaller than that for the reverse transition in a construct optimized for NMR studies. Simulations and native-state hydrogen-deuterium exchange NMR experiments suggest that fold switching can involve both partially and completely unfolded intermediates. The simulations predict that the transition state for fold switching coincides with isomerization of conserved prolines in the most rapidly exchanging region, and we confirm experimentally that proline isomerization is a rate-limiting step for fold switching. We explore the implications of our results for temperature compensation, a hallmark of circadian clocks, through a kinetic model.

Keywords: NMR; circadian clock; molecular dynamics; protein folding; temperature compensation

DOI: https://doi.org/10.1073/pnas.2412327121

J Exp Zool A Ecol Integr Physiol. 2024 Dec 11.

Seasonal mRNA Expression of Circadian Clock Genes in the Lizard Brain.

Taylor L Grossen, Alexus Bunnam, Rachel E Cohen.

Seasonally breeding animals undergo physiological and behavioral changes to time reproduction to occur during specific seasons. These changes are regulated by changing environmental conditions, which may be communicated to the brain using the central circadian clock. This clock consists of a daily oscillation in the expression of several core genes, including period (per), cryptochrome (cry), circadian locomotor output cycles kaput (clock), and basic helix-loop-helix ARNT-like protein 1 (bmal1). We began to examine seasonal regulation of four core circadian clock genes in a dissection of the reptile brain containing the hypothalamus-per1, cry1, bmal1 and clock. Our study focused on examining mRNA expression in the morning and compared levels between breeding and nonbreeding animals. We found that per1 and bmal1 mRNA expression was highest in the nonbreeding compared to breeding season in the anole hypothalamus. We also found that cry1 mRNA expression was higher in the female compared to the male anole hypothalamus. We found support for the idea that core circadian genes play a role in regulating changes between the seasons and/or sexes, although more work is needed to elucidate what processes might be differentially regulated. To our knowledge, this is the first examination of the expression of these four genes in the reptilian brain.

Keywords: bmal1; circadian clock; clock; cry; green anole; per1; reptile

DOI: https://doi.org/10.1002/jez.2889

Cell Mol Gastroenterol Hepatol. 2024 Dec 10. pii: S2352-345X(24)00195-4. [Epub ahead of print] 101440

Time-restricted feeding reinforces gut rhythmicity by restoring rhythms in intestinal metabolism in a jetlag mouse model.

Hui Leng, Theo Thijs, Louis Desmet, Guillaume Vanotti, Mona Farhadipour, Inge Depoortere.

BACKGROUND & AIMS: Circadian disturbances result in adverse health effects, including gastrointestinal symptoms. We investigated which physiological pathways in jejunal mucosa were disrupted during chronic jetlag and prevented during time-restricted feeding (TRF). Enteroids from Bmal1+/+ and Bmal1-/- mice were used to replicate the processes that were affected by chronic jetlag and rescued by TRF.
METHODS: C57BL/6J male mice were subjected to chronic jetlag or night-TRF for 4 weeks. An around-the-clock bulk-RNA sequencing study was performed on the jejunal mucosa. Bmal1+/+ and Bmal1-/- mouse enteroids were generated to study the jejunal epithelial clock dependency of rhythmic jejunal processes.
RESULTS: Chronic jetlag disrupted the rhythmicity of jejunal clock genes and the jejunal transcriptome which was partially rescued by TRF. Genes whose rhythm was altered by chronic jetlag but prevented by TRF were primarily associated with nutrient transport, lipid metabolism, ketogenesis and cellular organization. In vivo, chronic jetlag caused a phase shift in the rhythmic accumulation of neutral lipids and induced a diurnal rhythm in the number of crypt epithelial cells, both of which were prevented by TRF. In vitro, enteroids replicated the in vivo rhythmic accumulation of neutral lipids in a clock-dependent manner, while the rhythm of S phase proliferation was ultradian in both genotypes of enteroids.
CONCLUSIONS: This pioneering transcriptomic study demonstrates that TRF acts as a robust entrainer during chronic jetlag, realigning disturbances in the circadian clock and the transcriptome involved in metabolic functions in the jejunal mucosa. Enteroids can replicate the rhythmic accumulation of neutral lipids dependent on the jejunal epithelial clock, enabling these functions to be studied in vitro.

Keywords: chronic jetlag; circadian rhythms; jejunal metabolism; mouse enteroid; time-restricted feeding

DOI: https://doi.org/10.1016/j.jcmgh.2024.101440