npj Biological Timing and Sleep最新文献

The liver, a key metabolic organ, shows clear day-night variation in gene and protein expression, and in metabolic pathway activity. Liver cells possess molecular circadian clocks, but systemic factors are critical contributors to the circadian rhythmicity of liver gene expression. Glucocorticoid action is reported to be one such factor. Glucocorticoids are essential hormones, with strong circadian oscillations, which control multiple cellular processes via the glucocorticoid receptor (GR). We compare clock factor and GR binding at promoters and enhancers linked to rhythmic genes and find increased clock factor binding at those promoter elements where GR is also present. Genes with GR binding at the promoter are more highly expressed and more likely to be detected as rhythmic. We then test the role of GR directly, by profiling rhythmic gene expression in mice with/without hepatocyte-targeted GR deletion. Notably, we observe only a small effect of GR deletion, with most rhythmic genes showing unchanged rhythmicity, despite evidence for local GR binding. We find a small number of genes showing lost or gained rhythmicity with GR deletion; genes which lose rhythmicity associate with GR binding sites. Contrary to expectations, GR appears redundant for conveying timing information to most of the rhythmic liver transcriptome.

Circadian rhythms align biological processes with environmental cycles to enhance fitness. Eukaryotic circadian oscillators rely on transcriptional-translational feedback loops, although specific oscillator components vary among lineages. The plant oscillator consists of a uniquely complex network of transcriptional regulators. These clock genes regulate each other's expression and influence key developmental processes such as the transition from vegetative to reproductive growth. Here, we investigate the function of XAP5 CIRCADIAN TIMEKEEPER (XCT), a protein conserved across eukaryotes and previously implicated in RNA processing and circadian regulation in Arabidopsis thaliana. We show that XCT genetically and physically interacts with CONSTITUTIVE PHOTOMORPHOGENIC 1 (COP1), an E3 ubiquitin ligase also conserved across eukaryotes. Both XCT and COP1 regulate the abundance and activity of the oscillator component EARLY FLOWERING3 (ELF3) to modulate circadian function and flowering time. These findings demonstrate how broadly conserved factors collaborate with plant-specific regulators to maintain circadian integrity and coordinate developmental timing.

Circadian clocks coordinate physiology with daily cycles. Loss of circadian components disrupts bodily functions, but the phenotypes differ when disruption occurs during development or adulthood. Here, we compare effects of manipulating mammalian clock proteins across life stages, reviewing roles of BMAL1 and REV-ERBα/β in embryogenesis-skeletal formation, metabolic programming, cardiovascular development-and adulthood-tissue integrity, metabolic adaptation, neuroprotection. We further discuss mechanisms for dual involvement, and implications for stage-specific therapies.

Though circadian locomotor rhythms are primarily driven by the suprachiasmatic nucleus, voluntary motor behavior also requires dopaminergic neuron (DAN) activity. However, it is unknown whether DAN molecular and electrophysiological properties and rhythmic motor behaviors are dependent on a molecular clock. Here, we show substantia nigra pars compacta (SNc) and ventral tegmental area (VTA) DANs rhythmically express clock genes, and conditional deletion of Bmal1 in DANs reduces motivated locomotion without robust cell loss or gross motor impairment. Further, DAN Bmal1 conditional deletion disrupts 24-h rhythms in spike rate, revealing ultradian rhythms (~4-8 h). Lastly, SNc DAN bursting varies across time of day and increased early night bursting is dependent on the molecular clock and L-type calcium channel activation. Collectively, we provide evidence of a cell-intrinsic dopaminergic clock which regulates key behaviors and physiology. Future studies should consider the contribution of disrupted DAN molecular clocks in age-related motor diseases like Parkinson's Disease.

Seasonal responses can be triggered by photoperiod changes. To explain photoperiodic time measurement, three main models (hourglass, external coincidence, and internal coincidence) have been proposed based on physiological observations in plants and animals. It has been discussed which model fits best to explain each response. Studies in model plants like Arabidopsis and rice suggest their photoperiodic mechanisms incorporate features that fit more than one of these models.

Interbreeding between modern humans and archaic hominins, including Neanderthals and Denisovans, occurred as modern humans migrated outside of Africa. Here, we report on evidence of adaptive introgression from archaic hominins within genomic regions associated with circadian rhythm cycling, chronotype, and sleep using 76 worldwide modern human populations from the Human Genome Diversity Project and 1000 Genomes Project. We identified 265 independent segments suggestive of adaptive introgression, where 22 of these segments show evidence of positive selection. We tested for evidence of a latitudinal cline within 35 core haplotypes, finding no clear latitude gradient, and identified the likely archaic donor for each of these haplotypes. We found that several genes with evidence of adaptive introgression are associated with affective disorders, chronotype, and respiratory diseases. Lastly, many of the variants are eQTLs for several genes that are significantly enriched in immunity pathways.

Long-term exposure to nonstandard work schedules can result in circadian misalignment, which has been linked to a series of maladies. To test whether modulating light patterns reduces shiftwork-induced rest/activity disruptions, 30 male C57BL/6 J mice individually housed in cages outfitted with running wheels were exposed to 6 simulated shiftwork light interventions. Mice experiencing high light levels during shiftwork exhibited a significant decrease in activity compared to low light levels during shiftwork and a conventional 12 L:12D condition, indicating circadian misalignment. In contrast, mice experiencing shiftwork in darkness combined with either modulated evening light pulses or circadian blind, vision-permissive light showed similar levels of rest/activity compared to a 12 L:12D condition, with phasor analysis indicating that their 24-h circadian rest/activity patterns were not misaligned. The results show that exposure to light that permits visibility but is below activation of the circadian system during shiftwork can prevent circadian misalignment.

Circadian rhythms play a preeminent role in our life, organizing our physiology and behavior on a daily basis to resonate with our fluctuating environment. However, recent studies reveal that hundreds of mouse and human genes are expressed with a 12-h pattern. We take a close look at mammalian 12-h rhythms, their potential mechanisms and functions, and evidence linking them to circatidal rhythms, which enable marine animals to adapt to tides.

The two-process model (2pm) of sleep regulation is a conceptual framework and consists of mathematical equations. It shares similarities with models for cardiac, respiratory and neuronal rhythms and falls within the wider class of coupled oscillator models. The 2pm is related to neuronal mutual inhibition models of sleep-wake regulation. The mathematical structure of the 2pm, in which the sleep-wake cycle is entrained to the circadian pacemaker, explains sleep patterns in the absence of 24 h time cues, in different species and in early childhood. Extending the 2pm with a process describing the response of the circadian pacemaker to light creates a hierarchical entrainment system with feedback which permits quantitative modelling of the effect of self-selected light on sleep and circadian timing. The extended 2pm provides new interpretations of sleep phenotypes and provides quantitative predictions of effects of sleep and light interventions to support sleep and circadian alignment in individuals, including those with neurodegenerative disorders.

This review describes how transcriptomic/proteomic studies have contributed identifying molecular markers of sleep homeostasis and offers a perspective on the need to interrogate more comprehensively different dynamics, brain regions, and cell types. Modifications in molecular dynamics with development/aging are also emphasized. We suggest the concept of sleep homeostasis to be regarded as a variety of homeostats (not a single one) serving different functions for the brain across the lifespan.