bims-ciryme 2026-05-24 papers

J Cell Biol. 2026 Jun 01. pii: e202509044. [Epub ahead of print]225(6):

Core clock protein subcellular dynamics coordinate local and global circadian control in syncytia.

Ziyan Wang, Bradley M Bartholomai, Bin Wang, David Ritz, Daniel Schultz, Jennifer J Loros, Jay C Dunlap.

Circadian rhythms are pervasive among eukaryotes, and the underlying clocks share a common regulatory architecture-a negative feedback loop. A wealth of genetic and biochemical data underpin current perceptions of circadian oscillators but aspects of their cell biology remain cryptic, especially in syncytial systems like Neurospora crassa. We employed novel microfluidic systems and a light-blind mutant that retains circadian function to simultaneously track multiple clock components in vivo across circadian cycles in Neurospora. Despite heterogeneity of clock gene (frq) expression, we find robust, synchronous cycles in FRQ nuclear localization among all nuclei and document free diffusion of multiple clock components among nuclei. Within nuclei, clock components form small, highly dynamic nuclear bodies that persist throughout the cycle and exhibit time-dependent changes in composition, including transient colocalization between the positive and negative components for circadian regulatory functions. This rich context of in vivo spatiotemporal information illustrates how dynamic subnuclear organization and internuclear exchange of clock proteins ensure synchronous regulation of cellular activities across a macroscopic, multinucleated syncytium.

DOI: https://doi.org/10.1083/jcb.202509044

Genetics. 2026 May 18. pii: iyag126. [Epub ahead of print]

Rhythmic Nuclear Import Mediated by Importins Regulates the Neurospora Circadian Clock.

Ziyan Wang, Bin Wang, Bradley M Bartholomai, Jennifer J Loros, Jay C Dunlap.

Circadian clocks in eukaryotes rely on precisely regulated negative feedback loops to generate daily rhythms. However, the delay mechanisms that extend this structurally simple feedback loop to ∼24 hours are not yet fully understood. In the filamentous fungal model organism Neurospora crassa, the negative arm complex, centered by FREQUENCY (FRQ), must enter the nucleus to repress the White Collar Complex (WCC) and close the feedback loop, but the mechanisms and dynamics of its nuclear transport have remained unresolved. Using long-term live-cell imaging and fluorescence recovery after photobleaching (FRAP), we demonstrate that FRQ nuclear import is an active circadian-regulated process that is fastest early in the subjective day and whose rate progressively decreases as nuclear FRQ approaches peak levels, corresponding to altered direct binding between FRQ and Importin α. We further establish that Importin α is required for the spatial regulation of FRQ and WCC, as well as the correct timing of Neurospora circadian clock, whereas the nuclear accumulation of non-clock-related free WC-2 doesn't require Importin α. Analysis of the three Neurospora Importin β homologs reveals that each of them contributes differently to the circadian clock through pathways beyond FRQ or WCC nuclear import. More specifically, we find a genetic interaction between Importin β3 and the phosphatase PPH-4. Together, these findings indicate that nuclear import is a selective, dynamic, and rate-limiting regulatory step in the fungal circadian clock and reveal both conserved and fungal-specific mechanisms by which importins tune circadian timing.

Keywords: FRAP; FREQUENCY (FRQ); Fluorescent live-cell imaging; White Collar Complex (WCC); fungi; nucleocytoplasmic transportation

DOI: https://doi.org/10.1093/genetics/iyag126

Nat Commun. 2026 May 22.

Genetic variants affect diurnal glucose levels throughout the day.

FinnGen

Circadian rhythms not only coordinate the timing of wake and sleep but also regulate homeostasis within the body, including glucose metabolism. The genetic variants that contribute to the temporal control of glucose levels have not been previously examined. Using genome-wide data from ~420,000 individuals from the UK Biobank and replication in ~100,000 individuals from the Estonian Biobank, ~500,000 from FinnGen, ~160,000 from the VA Million Veteran Program, and ~52,000 from the MGB Biobank, we show that glucose levels are under diurnal genetic control. We discover a robust temporal association of glucose levels at the Melatonin receptor 1B (MTNR1B, rs10830963, P = 1×10-22) and a canonical circadian pacemaker gene Cryptochrome 2 (CRY2) loci (rs12419690, P = 1×10-16). Furthermore, we show that sleep modulates glucose levels, and the genetic variants have an independent role in diurnal glucose control. Finally, we show that these variants independently modulate risk of type 2 diabetes and that sleep medications including melatonin associate with type 2 diabetes. Our findings, together with earlier genetic and epidemiological evidence, show a clear connection between sleep and metabolism and highlight genetic variation at MTNR1B and CRY2 in the control of diurnal glucose levels.

DOI: https://doi.org/10.1038/s41467-026-72432-6

Sci Rep. 2026 May 21.

Internal desynchrony of the hepatic circadian system with dissociated systemic rhythms in middle-aged mice under social jet lag-like conditions.

Saki Fukushima, Dan Yang, Tatsumi Morita, Kenshiro Aragane, Sae Yamakawa, Kaito Kurogi, Ryohei Matsuo, Tiantian Ma, Keisuke Ikegami, Mitsuhiro Furuse, Shinobu Yasuo.

Social jet lag (SJL) leads to a misalignment between the circadian clock and social time. In this study, we investigated the effects of weekly shifts in light-dark (LD) conditions: two days per week with 6-h delayed LD cycles (simulating Saturday and Sunday). Core body temperature rhythms rapidly entrained to the delayed LD cycles on weekends, and these delayed rhythms persisted even after the LD cycle was advanced on Monday. In contrast, plasma corticosterone rhythms on Mondays did not show marked delays. In the livers of SJL mice on Monday, the expression rhythms of Per1, Per2, and Hsp70 were delayed compared to that in controls, whereas Rev-erbα expression rhythms remained comparable to those of the controls. The expression of lipid and glucose metabolism-related genes showed either delayed rhythms or no significant changes. In ex vivo experiments using liver slices, high-temperature stimulation induced Per2 and Hsp70 expression, while dexamethasone induced Per1 expression. High temperature and dexamethasone affected distinct sets of genes, and these responses were altered by weekly shifts in LD cycles. Overall, our findings indicate that weekly shifts in LD cycles induce internal desynchronization within the hepatic clock and metabolic pathways, possibly through uncoupling systemic circadian signals and gene-specific responses to stimuli.

Keywords: Body temperature; Circadian clock; Clock genes; Jet lag; Liver; Metabolism

DOI: https://doi.org/10.1038/s41598-026-53698-8

Nat Commun. 2026 May 22.

Intracellular potassium levels orchestrate circadian rhythmicity and cell division.

Sergio Gil Rodríguez, Louise L Hansen, Olivia J P Fraser, Yen Peng Chew, Rebecca K Spangler, Ellen Grünewald, Andrew D Beale, Beverley M Rabbitts, Alessandra Stangherlin, John S O'Neill, Carrie L Partch, Priya Crosby, Gerben van Ooijen.

Circadian (~24 h) rhythms are a fundamental feature of life, and their disruption increases the risk of infectious diseases, metabolic disorders, and cancer. We previously identified circadian oscillations in intracellular potassium concentrations in cells across kingdoms. Using highly divergent eukaryotic cell types, we now show that potassium levels act to regulate the period and phase of clock gene expression rhythms, therefore establishing intracellular potassium as a bona fide regulator of cellular circadian rhythms. Intracellular potassium also regulates critical events in the cell cycle. Strikingly, we observe that manipulating potassium levels inhibits cell proliferation in a circadian phase-dependent manner. As the timing of cell division is tuned by the circadian clock, we hypothesised that potassium rhythms could mechanistically link cell proliferation rhythms to the circadian cycle. In line with this hypothesis, we find that potassium levels are not only sufficient to instruct the timing of cell proliferation, but also essential to maintain coherent coupling between circadian rhythms and proliferation rhythms. These results establish circadian potassium rhythms as a primary factor coupling the cell- and circadian cycles in eukaryotic cells.

DOI: https://doi.org/10.1038/s41467-026-73351-2