bims-ciryme 2026-10-11 papers

Nat Commun. 2026 Sep 08. pii: 10627. [Epub ahead of print]17(1):

Role of PER-WDR5 interactions in the mammalian circadian clock.

Arne Börgel, Florian Hof, Mareen Welzel, Audrey Rawleigh, Marcel Wedemann, Rafaela Mororo Cavalcanti Keller, Vanessa Maissl, Kyra Ricci, Sandra Schick, Helen L May-Simera, Steven Brown, Achim Kramer, Katja Luck, Jürgen A Ripperger, Eva Wolf.

In the mammalian circadian clock, the transcription factor CLOCK/BMAL1 cycles between an active state recruiting co-activators like MLL1 and repressed states associated with PER1/2 and CRY1/2 clock proteins. The MLL1 complex component WDR5 was also found in a repressive PER complex. Here we show that WDR5 directly binds to the CRY binding domain (CBD) regions of PER1 and PER2. PER2 binds WDR5 via a WBM motif within the PER2/CRY interface, imposing competition between PER2/WDR5-, PER2/CRY- and RbBP5/WDR5 complexes. PER1 binds WDR5 predominantly via a WIN motif outside the CBD, enabling formation of trimeric PER1WIN/WDR5/RbBP5WBM - and PER1/WDR5/CRY complexes. WDR5 WIN site inhibitors weaken PER1/WDR5 interactions and impact cellular Bmal1- and Per2 expression dependent on the PER1 WIN motif, likely modulating the primary BMAL1/CLOCK/PER/CRY- and secondary BMAL1/REV-ERB/ROR circadian feedback loop. Together, our studies revealed a role of WDR5 as a direct PER interaction partner with critical differences between PER1 and PER2.

DOI: https://doi.org/10.1038/s41467-026-77583-0

NPJ Biol Timing Sleep. 2026 Oct 07. pii: 49. [Epub ahead of print]3(1):

Attractive and repulsive couplings between circadian pacemaker neurons promote entrainment to light-dark cycles with after-effect.

Yuta Kitaguchi, Satoru Komori, Hajime Tei, Koichiro Uriu.

The mammalian circadian pacemaker, the suprachiasmatic nucleus (SCN), comprises a core region that receives light signals from the retina and a shell region that outputs pacemaking rhythms to peripheral tissues. The free-running period (FRP) of animals in constant darkness (DD) correlates with the period of the preceding LD cycle, a phenomenon known as after-effect. To elucidate the mechanisms underlying robust entrainment and after-effect, we analyzed phase oscillator models incorporating attractive and repulsive couplings that respectively decrease or increase phase differences between oscillators. Attractive coupling from the core to shell regions accounts for experimentally observed phase relationships between these regions under LD cycles. Remarkably, repulsive coupling from the shell to core regions promotes SCN entrainability to LD cycles. Furthermore, after transfer to DD, the FRP slowly returns to the intrinsic SCN period, reflecting the after-effect. Our analysis identifies an SCN coupling architecture that underlies stable daily activity rhythms.

DOI: https://doi.org/10.1038/s44323-026-00112-1

Trends Neurosci. 2026 Sep 22. pii: S0166-2236(26)00184-0. [Epub ahead of print]

A microglial circadian clock sculpts synapses during neurodevelopment.

Annemarie J Carver, Nicole R Zürcher, Evan A Bordt.

In a recent study, Routh and colleagues demonstrated that the circadian clock regulates microglia-directed synaptic refinement during a critical period of neurodevelopment in mice, in a sex-dependent manner. Loss of the major circadian rhythm regulator, Bmal1, in microglia induced a proinflammatory state and excessive pruning of synapses, primarily in adolescent male mice.

Keywords: Bmal1; adolescence; dendritic spine; hippocampus; phagocytosis; sex differences

DOI: https://doi.org/10.1016/j.tins.2026.09.002

Front Endocrinol (Lausanne). 2026 ;17 1934310

Night-shift work is associated with peripheral clock gene dysregulation and circadian transcriptional network remodeling in female healthcare workers.

Silvia Vivarelli, Luca Falzone, Francesca Simona Fiorino, Federica Giambò, Massimo Libra, Concettina Fenga.

Background: Night-shift work disrupts the circadian-melatonin axis through chronic light-at-night exposure and has been associated with metabolic, inflammatory, cardiovascular, and cancer-related disorders, but peripheral molecular signatures of occupational chronodisruption remain incompletely characterized. Female healthcare workers (HCWs), frequently exposed to prolonged night-shift schedules, represent a relevant study population. In a previous computational study, we identified a deregulated circadian gene panel (CLOCK, TEF, PER1, and PER3) suggestive of transcriptional remodeling in exposed workers. Here, we experimentally validated this signature and investigated the non-canonical circadian transcription factor YY1.
Methods: Ninety-three female HCWs (47 day-shift, DSW; 46 night-shift workers, NSW) participated in the study. Peripheral blood expression of CLOCK, TEF, PER1, PER3, and YY1 was quantified by RT-qPCR. Associations with shift-work status and exposure metrics were evaluated using multivariable regression models adjusted for demographic, reproductive, lifestyle, and sleep-related covariates. Correlation, principal component, and clustering analyses were used to characterize transcriptional organization.
Results: Compared with DSW, NSW exhibited significantly lower expression of CLOCK (p = 0.0362), TEF (p < 0.0001), and PER1 (p = 0.0003), whereas PER3 expression was unchanged (p = 0.7978). TEF and CLOCK expression progressively declined with longer duration and higher cumulative night-shift exposure. TEF showed excellent in-sample discrimination between groups (AUC = 0.925), while a four-gene model achieved an AUC of 0.940. YY1 expression was reduced in NSW (p = 0.0019), decreased across long-duration and high-exposure categories, and further improved multigene classification performance (AUC = 0.976). Network analyses revealed disrupted coordination among CLOCK, TEF, and PER1, whereas PER3 maintained stable expression despite reduced integration within the transcriptional network.
Conclusions: Night-shift work exposure is associated with coordinated downregulation of CLOCK, TEF, and PER1, altered transcriptional network organization, and reduced YY1 expression. While PER3 expression is preserved, its network connectivity is selectively weakened in exposed workers. These findings identify peripheral transcriptional signatures that may provide a basis for future biomarker development and exposure characterization and support further investigation of chronobiology-driven preventive strategies within a precision medicine framework.

Keywords: biomarkers; chronodisruption; circadian rhythm; clock genes; gene expression profiling; healthcare workers; night-shift work; occupational health

DOI: https://doi.org/10.3389/fendo.2026.1934310