bims-ciryme 2020-11-01 papers

Proc Natl Acad Sci U S A. 2020 Oct 26. pii: 202003524. [Epub ahead of print]

Wake-sleep cycles are severely disrupted by diseases affecting cytoplasmic homeostasis.

Stephen Beesley, Dae Wook Kim, Matthew D'Alessandro, Yuanhu Jin, Kwangjun Lee, Hyunjeong Joo, Yang Young, Robert J Tomko, John Faulkner, Joshua Gamsby, Jae Kyoung Kim, Choogon Lee.

The circadian clock is based on a transcriptional feedback loop with an essential time delay before feedback inhibition. Previous work has shown that PERIOD (PER) proteins generate circadian time cues through rhythmic nuclear accumulation of the inhibitor complex and subsequent interaction with the activator complex in the feedback loop. Although this temporal manifestation of the feedback inhibition is the direct consequence of PER's cytoplasmic trafficking before nuclear entry, how this spatial regulation of the pacemaker affects circadian timing has been largely unexplored. Here we show that circadian rhythms, including wake-sleep cycles, are lengthened and severely unstable if the cytoplasmic trafficking of PER is disrupted by any disease condition that leads to increased congestion in the cytoplasm. Furthermore, we found that the time delay and robustness in the circadian clock are seamlessly generated by delayed and collective phosphorylation of PER molecules, followed by synchronous nuclear entry. These results provide clear mechanistic insight into why circadian and sleep disorders arise in such clinical conditions as metabolic and neurodegenerative diseases and aging, in which the cytoplasm is congested.

Keywords: PERIOD; bistable phospho-switch; circadian rhythm; cytoplasmic trafficking; negative feedback loop

DOI: https://doi.org/10.1073/pnas.2003524117

Proc Natl Acad Sci U S A. 2020 Oct 26. pii: 201920653. [Epub ahead of print]

The human CRY1 tail controls circadian timing by regulating its association with CLOCK:BMAL1.

Gian Carlo G Parico, Ivette Perez, Jennifer L Fribourgh, Britney N Hernandez, Hsiau-Wei Lee, Carrie L Partch.

Circadian rhythms are generated by interlocked transcription-translation feedback loops that establish cell-autonomous biological timing of ∼24 h. Mutations in core clock genes that alter their stability or affinity for one another lead to changes in circadian period. The human CRY1Δ11 mutant lengthens circadian period to cause delayed sleep phase disorder (DSPD), characterized by a very late onset of sleep. CRY1 is a repressor that binds to the transcription factor CLOCK:BMAL1 to inhibit its activity and close the core feedback loop. We previously showed how the PHR (photolyase homology region) domain of CRY1 interacts with distinct sites on CLOCK and BMAL1 to sequester the transactivation domain from coactivators. However, the Δ11 variant alters an intrinsically disordered tail in CRY1 downstream of the PHR. We show here that the CRY1 tail, and in particular the region encoded by exon 11, modulates the affinity of the PHR domain for CLOCK:BMAL1. The PHR-binding epitope in exon 11 is necessary and sufficient to disrupt the interaction between CRY1 and the subunit CLOCK. Moreover, PHR-tail interactions are conserved in the paralog CRY2 and reduced when either CRY is bound to the circadian corepressor PERIOD2. Discovery of this autoregulatory role for the mammalian CRY1 tail and conservation of PHR-tail interactions in both mammalian cryptochromes highlights functional conservation with plant and insect cryptochromes, which also utilize PHR-tail interactions to reversibly control their activity.

Keywords: CON NMR; circadian rhythms; cryptochrome; delayed sleep phase disorder; intrinsically disordered protein

DOI: https://doi.org/10.1073/pnas.1920653117

Front Cell Dev Biol. 2020 ;8 587697

Stromal Expression of the Core Clock Gene Period 2 Is Essential for Tumor Initiation and Metastatic Colonization.

Lee Shaashua, Shimrit Mayer, Chen Lior, Hagar Lavon, Alexander Novoselsky, Ruth Scherz-Shouval.

The circadian clock regulates diverse physiological processes by maintaining a 24-h gene expression pattern. Genetic and environmental cues that disrupt normal clock rhythms can lead to cancer, yet the extent to which this effect is controlled by the cancer cells versus non-malignant cells in the tumor microenvironment (TME) is not clear. Here we set out to address this question, by selective manipulation of circadian clock genes in the TME. In two different mouse models of cancer we find that expression of the core clock gene Per2 in the TME is crucial for tumor initiation and metastatic colonization, whereas another core gene, Per1, is dispensable. We further show that loss of Per2 in the TME leads to significant transcriptional changes in response to cancer cell introduction. These changes may contribute to a tumor-suppressive microenvironment. Thus, our work unravels an unexpected protumorigenic role for the core clock gene Per2 in the TME, with potential implications for therapeutic dosing strategies and treatment regimens.

Keywords: MC38 colon cancer cells; Per2; chronobiology; circadian clock; colon cancer; liver; metastasis; tumor microenvironment

DOI: https://doi.org/10.3389/fcell.2020.587697

Front Neurosci. 2020 ;14 551843

Assessment of Sleep, K-Complexes, and Sleep Spindles in a T21 Light-Dark Cycle.

Scott H Deibel, Ryan Rota, Hendrik W Steenland, Karim Ali, Bruce L McNaughton, Masami Tatsuno, Robert J McDonald.

Circadian rhythm misalignment has a deleterious impact on the brain and the body. In rats, exposure to a 21-hour day length impairs hippocampal dependent memory. Sleep, and particularly K-complexes and sleep spindles in the cortex, have been hypothesized to be involved in memory consolidation. Altered K-complexes, sleep spindles, or interaction between the cortex and hippocampus could be a mechanism for the memory consolidation failure but has yet to be assessed in any circadian misalignment paradigm. In the current study, continuous local field potential recordings from five rats were used to assess the changes in aspects of behavior and sleep, including wheel running activity, quiet wakefulness, motionless sleep, slow wave sleep, REM sleep, K-complexes and sleep spindles, in rats exposed to six consecutive days of a T21 light-dark cycle (L9:D12). Except for a temporal redistribution of sleep and activity during the T21, there were no changes in period, or total amount for any aspect of sleep or activity. These data suggest that the memory impairment elicited from 6 days of T21 exposure is likely not due to changes in sleep architecture. It remains possible that hippocampal plasticity is affected by experiencing light when subjective circadian phase is calling for dark. However, if there is a reduction in hippocampal plasticity, changes in sleep appear not to be driving this effect.

Keywords: circadian misalignment; circadian rhythms; memory; rats; sleep

DOI: https://doi.org/10.3389/fnins.2020.551843

Sci Rep. 2020 Oct 29. 10(1): 18614

Circadian misalignment increases mood vulnerability in simulated shift work.

Sarah L Chellappa, Christopher J Morris, Frank A J L Scheer.

Night shift work can associate with an increased risk for depression. As night workers experience a 'misalignment' between their circadian system and daily sleep-wake behaviors, with negative health consequences, we investigated whether exposure to circadian misalignment underpins mood vulnerability in simulated shift work. We performed randomized within-subject crossover laboratory studies in non-shift workers and shift workers. Simulated night shifts were used to induce a misalignment between the endogenous circadian pacemaker and sleep/wake cycles (circadian misalignment), while environmental conditions and food intake were controlled. Circadian misalignment adversely impacted emotional state, such that mood and well-being levels were significantly decreased throughout 4 days of continuous exposure to circadian misalignment in non-shift workers, as compared to when they were under circadian alignment (interaction of "circadian alignment condition" vs. "day", mood: p < 0.001; well-being: p < 0.001; adjusted p-values). Similarly, in shift workers, mood and well-being levels were significantly reduced throughout days of misalignment, as compared to circadian alignment (interaction of "circadian alignment condition" vs. "day", mood: p = 0.002; well-being: p = 0.002; adjusted p-values). Our findings indicate that circadian misalignment is an important biological component for mood vulnerability, and that individuals who engage in shift work are susceptible to its deleterious mood effects.

DOI: https://doi.org/10.1038/s41598-020-75245-9