Rhythmic Gene Expression Research Articles

The genetically programmed rhythmic alteration of diurnal gene expression in the aged Arabidopsis leaves

The circadian clock regulates the daily pattern of temporal gene expression. In Arabidopsis, aging is associated with a shortening of the endogenous period of circadian rhythms under circadian conditions. However, the functional link between the circadian clock and aging under diurnal conditions and its physiological relevance remain elusive. In this study, we investigate and characterize the effect of aging on the waveforms of rhythmic gene expression patterns under light/dark cycles. Our analysis revealed that the diurnal rhythmic patterns of core clock genes undergo significant rhythmic alteration with phase shift and change of waveforms in aged plants compared to younger plants. Transcriptomic analysis indicated that this age-dependent rhythmic alteration occurs not only in core clock genes but also globally. Due to the rhythmic alteration patterns of the diurnal rhythmic gene expression, aged plants experience subjectively a shorter day and longer night. We also observed that genetic mutants of core clock component genes exhibited broadly yet distinctively altered changes in diurnal rhythmic gene expression patterns as aging progresses. Collectively, our findings support that age-dependent rhythmic alteration of diurnal gene expression rhythms reprograms the timetable of daily gene expression, leading to the physiological changes required for plant senescence.

A one-day journey to the suburbs: circadian clock in the Drosophila visual system.

Living organisms, which are constantly exposed to cyclical variations in their environment, need a high degree of plasticity in their visual system to respond to daily and seasonal fluctuations in lighting conditions. In Drosophila melanogaster, the visual system is a complex tissue comprising different photoreception structures that exhibit daily rhythms in gene expression, cell morphology, and synaptic plasticity, regulated by both the central and peripheral clocks. In this review, we briefly summarize the structure of the circadian clock and the visual system in Drosophila and comprehensively describe circadian oscillations in visual structures, from molecules to behaviors, which are fundamental for the fine-tuning of visual sensitivity. We also compare some features of the rhythmicity in the visual system with that of the central pacemaker and hypothesize about the differences in the regulatory signals and mechanisms that control these two clocks.

Interplay Between the Circadian Clock and Sirtuins

The circadian clock is an autonomous timekeeping system evolved by organisms to adapt to external changes, regulating a variety of important physiological and behavioral processes. Recent studies have shown that the sirtuin family of histone deacetylases is involved in regulating the expression of clock genes and plays an important role in maintaining the normal rhythm of clock gene expression and behavior. Moreover, sirtuins are regulated directly or indirectly by the circadian clock system. The mutual regulation between the circadian clock and sirtuins is likely involved in a variety of signal transduction and metabolism processes. In this review, we discuss the molecular mechanisms and research progress on the intertwined relationship between the circadian clock and sirtuins, mainly in mammals, highlighting sirtuins as molecular links between metabolic control and circadian rhythms and offering our perspectives on future developments in the field.

Detecting Rhythmic Gene Expression in Single-cell Transcriptomics.

An autonomous, environmentally synchronizable circadian rhythm is a ubiquitous feature of life on Earth. In multicellular organisms, this rhythm is generated by a transcription-translation feedback loop present in nearly every cell that drives daily expression of thousands of genes in a tissue-dependent manner. Identifying the genes that are under circadian control can elucidate the mechanisms by which physiological processes are coordinated in multicellular organisms. Today, transcriptomic profiling at the single-cell level provides an unprecedented opportunity to understand the function of cell-level clocks. However, while many cycling detection algorithms have been developed to identify genes under circadian control in bulk transcriptomic data, it is not known how best to adapt these algorithms to single-cell RNA seq data. Here, we benchmark commonly used circadian detection methods on their reliability and efficiency when applied to single-cell RNA seq data. Our results provide guidance on adapting existing cycling detection methods to the single-cell domain and elucidate opportunities for more robust and efficient rhythm detection in single-cell data. We also propose a subsampling procedure combined with harmonic regression as an efficient strategy to detect circadian genes in the single-cell setting.

Exenatide administration time-dependently affects the hepatic circadian clock through glucagon-like peptide-1 receptors in the central nervous system

Accumulating evidence indicates that disruption of the circadian clock contributes to the development of lifestyle-related diseases. We have previously shown that exenatide, a glucagon-like peptide-1 (GLP-1) receptor agonist, can strongly affect the molecular clocks in the peripheral tissues. This study aimed to investigate the effects of its dosing time and the central nervous system-specific GLP-1 receptor knockdown (GLP1RKD) on the hepatic clock in mice treated with exenatide. Male C57BL/6J and GLP1RKD mice were housed under a 12-h/12-h light/dark cycle, and feeding was restricted to either the light period (L-TRF) or the first 4 h in the dark period (D-TRF). In parallel, exenatide was administered 4–5 times, once daily either at the beginning of the dark (ZT 12) or light period (ZT 0), and we assessed the mRNA expression rhythms of clock genes in the liver thereafter. Exenatide administration at ZT 12 counteracted the phase shift effect of the L-TRF on the hepatic clock of wild-type mice, whereas the dosing at ZT 0 enhanced its effect. However, exenatide did not influence the phase of the hepatic clock under D-TRF regardless of the dosing time. The effect of exenatide in wild-type mice weakened in GLP1RKD mice. These results showed that exenatide dosing time-dependently affects the hepatic circadian clock through the central GLP-1 system. Exenatide administration at the beginning of the active period (i.e., in the morning for humans) might prevent disruption of the peripheral clocks caused by irregular eating habits.

Transcriptomic Plasticity of the Circadian Clock in Response to Photoperiod: A Study in Male Melatonin-Competent Mice.

Seasonal daylength, or circadian photoperiod, is a pervasive environmental signal that profoundly influences physiology and behavior. In mammals, the central circadian clock resides in the suprachiasmatic nuclei (SCN) of the hypothalamus where it receives retinal input and synchronizes, or entrains, organismal physiology and behavior to the prevailing light cycle. The process of entrainment induces sustained plasticity in the SCN, but the molecular mechanisms underlying SCN plasticity are incompletely understood. Entrainment to different photoperiods persistently alters the timing, waveform, period, and light resetting properties of the SCN clock and its driven rhythms. To elucidate novel candidate genes for molecular mechanisms of photoperiod plasticity, we performed RNA sequencing on whole SCN dissected from mice raised in long (light:dark [LD] 16:8) and short (LD 8:16) photoperiods. Fewer rhythmic genes were detected in mice subjected to long photoperiod, and in general, the timing of gene expression rhythms was advanced 4-6 h. However, a few genes showed significant delays, including Gem. There were significant changes in the expression of the clock-associated gene Timeless and in SCN genes related to light responses, neuropeptides, gamma aminobutyric acid (GABA), ion channels, and serotonin. Particularly striking were differences in the expression of the neuropeptide signaling genes Prokr2 and Cck, as well as convergent regulation of the expression of 3 SCN light response genes, Dusp4, Rasd1, and Gem. Transcriptional modulation of Dusp4 and Rasd1 and phase regulation of Gem are compelling candidate molecular mechanisms for plasticity in the SCN light response through their modulation of the critical NMDAR-MAPK/ERK-CREB/CRE light signaling pathway in SCN neurons. Modulation of Prokr2 and Cck may critically support SCN neural network reconfiguration during photoperiodic entrainment. Our findings identify the SCN light response and neuropeptide signaling gene sets as rich substrates for elucidating novel mechanisms of photoperiod plasticity. Data are also available at http://circadianphotoperiodseq.com/, where users can view the expression and rhythmic properties of genes across these photoperiod conditions.

Comparative transcriptomic rhythms in the mouse and human prefrontal cortex.

Alterations in multiple subregions of the human prefrontal cortex (PFC) have been heavily implicated in psychiatric diseases. Moreover, emerging evidence suggests that circadian rhythms in gene expression are present across the brain, including in the PFC, and that these rhythms are altered in disease. However, investigation into the potential circadian mechanisms underlying these diseases in animal models must contend with the fact that the human PFC is highly evolved and specialized relative to that of rodents. Here, we use RNA sequencing to lay the groundwork for translational studies of molecular rhythms through a sex-specific, cross species comparison of transcriptomic rhythms between the mouse medial PFC (mPFC) and two subregions of the human PFC, the anterior cingulate cortex (ACC) and the dorsolateral PFC (DLPFC). We find that while circadian rhythm signaling is conserved across species and subregions, there is a phase shift in the expression of core clock genes between the mouse mPFC and human PFC subregions that differs by sex. Furthermore, we find that the identity of rhythmic transcripts is largely unique between the mouse mPFC and human PFC subregions, with the most overlap (20%, 236 transcripts) between the mouse mPFC and the human ACC in females. Nevertheless, we find that basic biological processes are enriched for rhythmic transcripts across species, with key differences between regions and sexes. Together, this work highlights both the evolutionary conservation of transcriptomic rhythms and the advancement of the human PFC, underscoring the importance of considering cross-species differences when using animal models.

Time-specific lipid and gene expression responses to chilling stress in panicoid grass.

This article comments on: Kenchanmane Raju SK, Zhang Y, Mahboub S, Ngu DW, Qiu Y, Harmon FG, Schnable JC, Roston RL. 2024. Rhythmic lipid and gene expression responses to chilling in panicoid grasses. Journal of Experimental Botany 75, https://doi.org/10.1093/jxb/erae247

Circadian cilia transcriptome in mouse brain across physiological and pathological states

Primary cilia are dynamic sensory organelles that continuously undergo structural modifications in response to environmental and cellular signals, many of which exhibit rhythmic patterns. Building on our previous findings of rhythmic cilia-related gene expression in diurnal primates (baboon), this study extends the investigation to the nocturnal mouse brain to identify circadian patterns of cilia gene expression across brain regions. We used computational techniques and transcriptomic data from four publicly available databases, to examine the circadian expression of cilia-associated genes within six brain areas: brainstem, cerebellum, hippocampus, hypothalamus, striatum, and suprachiasmatic nucleus. Our analysis reveals that a substantial proportion of cilia transcripts exhibit circadian rhythmicity across the examined regions, with notable overrepresentation in the striatum, hippocampus, and cerebellum. We also demonstrate region-specific variations in the abundance and timing of circadian cilia genes’ peaks, indicating an adaptation to the distinct physiological roles of each brain region. Additionally, we show that the rhythmic patterns of cilia transcripts are shifted under various physiological and pathological conditions, including modulation of the dopamine system, high-fat diet, and epileptic conditions, indicating the adaptable nature of cilia transcripts’ oscillation. While limited to a few mouse brain regions, our study provides initial insights into the distinct circadian patterns of cilia transcripts and highlights the need for future research to expand the mapping across wider brain areas to fully understand the role of cilia’s spatiotemporal dynamics in brain functions.

Parenteral nutrition results in peripheral ileal to hepatic circadian discordance in mice.

We have developed a mouse model of parenteral nutrition-associated liver disease (PNALD) in which parenteral nutrition (PN) infusion results in cholestatic liver injury. In the liver, the master circadian genes Arntl/Bmal drive rhythmic gene expression and regulate circadian expression of hepatic functions including bile acid synthesis. The aim of this study was to examine the effect of continuous PN on ileal and hepatic expression of circadian regulatory (CR) genes, farnesoid X receptor (FXR) signaling, and bile acid synthesis in mice. Wild-type mice were exposed to ad libitum Chow or continuous soy oil lipid emulsion-based PN infusion through a central venous catheter for 4 days (PN). Water was provided ad libitum, but no nutrients were provided enterally. On day 4, separate groups of Chow and PN-fed mice were euthanized every 6 h (7 AM, 1 PM, 7 PM, and 1 AM), and ileal, hepatic tissue and serum harvested. From tissue samples, the relative expression of circadian transcription factors and FXR signaling was assessed. Administration of 4-day PN increased hepatic injury, inflammatory cytokine expression, and gut permeability. In the ileum, PN activated FXR and induced expression of Fgf15 and Nr0b2. In the liver, expression of FXR-downstream targets was dysregulated. PN administrations impacted hepatic and ileal circadian transcription factor mRNA expression, which was discordant between the two organs. Dysregulation of circadian regulatory machinery is in part due to discordance of the gut-liver axis during PN. Pharmacological targeting of CR as a therapeutic strategy for PNALD thus deserves further investigation.NEW & NOTEWORTHY This study used a novel short-term model of parenteral nutrition (PN) that is translationally relevant. We find that short-term PN is sufficient to induce hepatic and ileal changes in circadian transcription factor expression and to prevent normal concordant coordination of circadian transcription factors between the ileum and liver. These data suggest that targeting circadian transcription may have some clinical benefit in patients receiving parenteral nutrition.

Variational inference of single cell time series.

Time course single-cell RNA sequencing (scRNA-seq) enables researchers to probe genome-wide expression dynamics at the the single cell scale. However, when gene expression is affected jointly by time and cellular identity, analyzing such data - including conducting cell type annotation and modeling cell type-dependent dynamics - becomes challenging. To address this problem, we propose SNOW (SiNgle cell flOW map), a deep learning algorithm to deconvolve single cell time series data into time-dependent and time-independent contributions. SNOW has a number of advantages. First, it enables cell type annotation based on the time-independent dimensions. Second, it yields a probabilistic model that can be used to discriminate between biological temporal variation and batch effects contaminating individual timepoints, and provides an approach to mitigate batch effects. Finally, it is capable of projecting cells forward and backward in time, yielding time series at the individual cell level. This enables gene expression dynamics to be studied without the need for clustering or pseudobulking, which can be error prone and result in information loss. We describe our probabilistic framework in detail and demonstrate SNOW using data from three distinct time course scRNA-seq studies. Our results show that SNOW is able to construct biologically meaningful latent spaces, remove batch effects, and generate realistic time-series at the single-cell level. By way of example, we illustrate how the latter may be used to enhance the detection of cell type-specific circadian gene expression rhythms, and may be readily extended to other time-series analyses.

Altered circadian expression of clock genes and clock-regulatory epigenetic modifiers in saliva of children with fetal alcohol spectrum disorders

Prenatal alcohol-exposed (AE) infants and children often demonstrate disrupted sleep patterns, including more frequent awakenings, reduced total sleep time, and more night-to-night sleep variability. Despite the strong connection between sleep patterns and circadian rhythmicity, relatively little is known about circadian rhythm disruptions in individuals with AE. Recently, several reports demonstrated that evaluating the expression patterns of human clock genes in biological fluids could reveal an individual’s circadian phenotype. Human saliva offers an emerging and easily available physiological sample that can be collected non-invasively for core-clock gene transcript analyses. We compared the expression patterns of core-clock genes and their regulatory genes in salivary samples of children aged 6–10 years-old with and without AE during the light cycle between ZT0-ZT11. We isolated the RNA from the samples and measured the expression patterns of core clock genes and clock regulating genes using the human specific primers with quantitative real-time PCR. Analysis of core clock genes expression levels in saliva samples from AE children indicates significantly altered levels in expression of core-clock BMAL1, CLOCK, PER1-3 and CRY1,2, as compared to those in age-matched control children. We did not find any sex difference in levels of clock genes in AE and control groups. Cosinor analysis was used to evaluate the rhythmic pattern of these clock genes, which identified circadian patterns in the levels of core clock genes in the control group but absent in the AE group. The gene expression profile of a salivary circadian biomarker ARRB1 was rhythmic in saliva of control children but was arhythmic in AE children. Altered expression patterns were also observed in clock regulatory genes: NPAS2, NFL3, NR1D1, DEC1, DEC2, and DBP, as well as chromatin modifiers: MLL1, P300, SIRT1, EZH2, HDAC3, and ZR1D1, known to maintain rhythmic expression of core-clock genes. Overall, these findings provide the first evidence that AE disturbs the circadian patten expression of core clock genes and clock-regulatory chromatin modifiers in saliva.

Detecting Rhythmic Gene Expression in Single Cell Transcriptomics.

An autonomous, environmentally-synchronizable circadian rhythm is a ubiquitous feature of life on Earth. In multicellular organisms, this rhythm is generated by a transcription-translation feedback loop present in nearly every cell that drives daily expression of thousands of genes in a tissue-dependent manner. Identifying the genes that are under circadian control can elucidate the mechanisms by which physiological processes are coordinated in multicellular organisms. Today, transcriptomic profiling at the single-cell level provides an unprecedented opportunity to understand the function of cell-level clocks. However, while many cycling detection algorithms have been developed to identify genes under circadian control in bulk transcriptomic data, it is not known how best to adapt these algorithms to single-cell RNAseq data. Here, we benchmark commonly used circadian detection methods on their reliability and efficiency when applied to single cell RNAseq data. Our results provide guidance on adapting existing cycling detection methods to the single-cell domain, and elucidate opportunities for more robust and efficient rhythm detection in single-cell data. We also propose a subsampling procedure combined with harmonic regression as an efficient strategy to detect circadian genes in the single-cell setting.

Plant Circadian Clocks: Unravelling the Molecular Rhythms of Nature

The circadian clock is a fundamental biological mechanism that allows organisms to synchronize their internal processes with the external environment, thereby optimizing growth, development, and physiology. In plants, circadian rhythms govern various aspects of their life cycle, including germination, leaf movement, flowering, and responses to environmental cues such as light and temperature. Understanding the molecular mechanisms underlying plant circadian clocks is essential not only for elucidating fundamental principles of plant biology but also for applications in agriculture and biotechnology. This review delves into the intricate molecular networks that comprise plant circadian clocks, focusing on key components and their interactions. At the core of these clocks are transcription-translation feedback loops (TTFLs) involving a set of clock genes. The central oscillator, composed of genes such as CIRCADIAN CLOCK ASSOCIATED 1 (CCA1), LATE ELONGATED HYPOCOTYL (LHY), TIMING OF CAB EXPRESSION 1 (TOC1), and PSEUDO-RESPONSE REGULATOR (PRR) genes, drives rhythmic expression of downstream clock-controlled genes (CCGs). The interplay between positive and negative regulators within the TTFLs generates robust oscillations with a period of approximately 24 hours. Additionally, post-translational modifications, protein-protein interactions, and chromatin remodeling contribute to fine-tuning the circadian system, allowing plants to adapt to changing environmental conditions. Light perception through photoreceptors such as phytochromes and cryptochromes plays a crucial role in entraining the circadian clock to external cues, ensuring synchronization with the day-night cycle. Furthermore, recent advancements in omics technologies, including genomics, transcriptomics, proteomics, and metabolomics, have provided unprecedented insights into the complexity and plasticity of plant circadian clocks. Integration of multi-omics data has facilitated the construction of comprehensive regulatory networks and computational models, enabling predictive understanding of clock function and behavior under diverse conditions. Overall, unraveling the molecular rhythms of plant circadian clocks not only enhances our knowledge of fundamental biological processes but also holds promise for improving crop productivity, stress resilience, and sustainability in agriculture through targeted manipulation of clock components and their associated pathways. Future research endeavors will undoubtedly continue to unveil the intricacies of these fascinating timekeeping mechanisms, further enriching our understanding of the molecular rhythms of nature.

Human genetic variation determines 24-hour rhythmic gene expression and disease risk.

24-hour biological rhythms are essential to maintain physiological homeostasis. Disruption of these rhythms increases the risks of multiple diseases. The biological rhythms are known to have a genetic basis formed by core clock genes, but how individual genetic variation shapes the oscillating transcriptome and contributes to human chronophysiology and disease risk is largely unknown. Here, we mapped interactions between temporal gene expression and genotype to identify quantitative trait loci (QTLs) contributing to rhythmic gene expression. These newly identified QTLs were termed as rhythmic QTLs (rhyQTLs), which determine previously unappreciated rhythmic genes in human subpopulations with specific genotypes. Functionally, rhyQTLs and their associated rhythmic genes contribute extensively to essential chronophysiological processes, including bile acid and lipid metabolism. The identification of rhyQTLs sheds light on the genetic mechanisms of gene rhythmicity, offers mechanistic insights into variations in human disease risk, and enables precision chronotherapeutic approaches for patients.

Targeting the liver clock improves fibrosis by restoring TGF-β signaling

Liver fibrosis is the major driver of hepatocellular carcinoma and liver disease-related death. Approved antifibrotic therapies are absent and compounds in development have limited efficacy. Increased TGF-β signaling drives collagen deposition by hepatic stellate cells (HSCs)/myofibroblasts. Here, we aimed to dissect the role of the circadian clock (CC) in controlling TGF-β signaling and liver fibrosis. Using CC-mutant mice, enriched HSCs and myofibroblasts obtained from healthy and fibrotic mice in different CC phases and loss-of-function studies in human hepatocytes and myofibroblasts, we investigated the relationship between CC and TGF-β signaling. We explored hepatocyte-myofibroblast communication through bioinformatic analyses of single-nuclei transcriptomes and performed validation in cell-based models. Using mouse models for MASH (metabolic dysfunction-associated steatohepatitis)-related fibrosis and spheroids from patients with liver disease, we performed proof-of-concept studies to validate pharmacological targetability and clinical translatability. We discovered that the CC oscillator temporally gates TGF-β signaling and this regulation is broken in fibrosis. We demonstrate that HSCs and myofibroblasts contain a functional CC with rhythmic expression of numerous genes, including fibrogenic genes. Perturbation studies in hepatocytes and myofibroblasts revealed a reciprocal relationship between TGF-β activation and CC perturbation, which was confirmed in patient-derived exvivo and invivo models. Pharmacological modulation of CC-TGF-β signaling inhibited fibrosis in mouse models invivo as well as in patient-derived liver spheroids. The CC regulates TGF-β signaling, and the breakdown of this control is associated with liver fibrosis in patients. Pharmacological proof-of-concept studies across different models have uncovered the CC as a novel therapeutic target for liver fibrosis - a growing unmet medical need. Liver fibrosis due to metabolic diseases is a global health challenge. Many liver functions are rhythmic throughout the day, being controlled by the circadian clock (CC). Here we demonstrate that regulation of the CC is perturbed upon chronic liver injury and this perturbation contributes to fibrotic disease. By showing that a compound targeting the CC improves liver fibrosis in patient-derived models, this study provides a novel therapeutic candidate strategy to treat fibrosis in patients. Additional studies will be needed for clinical translation. Since the findings uncover a previously undiscovered profibrotic mechanism and therapeutic target, the study is of interest for scientists investigating liver disease, clinical hepatologists and drug developers.

The Estrous Cycle Coordinates the Circadian Rhythm of Eating Behavior in Mice.

The estrous cycle regulates rhythms of locomotor activity, body temperature, and circadian gene expression. In female mice, activity increases on the night of proestrus, when elevated estrogens cause ovulation. Exogenous estradiol regulates eating behavior rhythms in female mice fed a high-fat diet, but it is unknown whether endogenous estrogens regulate eating rhythms. In this study, we investigated whether diurnal and circadian eating behavior rhythms change systematically across the estrous cycle. We first studied diurnal eating behavior rhythms in female C57BL/6J mice in 12L:12D. Estrous cycle stages were determined by vaginal cytology while eating behavior and wheel revolutions were continuously measured. The mice had regular 4- to 5-day estrous cycles. Consistent with prior studies, the greatest number of wheel revolutions occurred on the night of proestrus into estrus when systemic levels of estrogens peak. The amplitude, or robustness, of the eating behavior rhythm also fluctuated with 4- to 5-day cycles and peaked primarily during proestrus or estrus. The phases of eating behavior rhythms fluctuated, but not at 4- or 5-day intervals, and phases did not correlate with estrous cycle stages. After ovariectomy, the eating behavior rhythm amplitude fluctuated at irregular intervals. In constant darkness, the amplitude of the circadian eating behavior rhythm peaked every 4 or 5 days and coincided with the circadian day that had the greatest number of wheel revolutions, a marker of proestrus. These data suggest that fluctuations of ovarian hormones across the estrous cycle temporally organize the robustness of circadian eating behavior rhythms so that it peaks during ovulation and sexual receptivity.

BMAL1-HIF2α heterodimers contribute to ccRCC.

Circadian disruption enhances cancer risk, and many tumors exhibit disordered circadian gene expression. We show rhythmic gene expression is unexpectedly robust in clear cell renal cell carcinoma (ccRCC). Furthermore, the clock gene BMAL1 is higher in ccRCC than in healthy kidneys, unlike in other tumor types. BMAL1 is closely related to ARNT, and we show that BMAL1-HIF2α regulates a subset of HIF2α target genes in ccRCC cells. Depletion of BMAL1 reprograms HIF2α chromatin association and target gene expression and reduces ccRCC growth in culture and in xenografts. Analysis of pre-existing data reveals higher BMAL1 in patient-derived xenografts that are sensitive to growth suppression by a HIF2α antagonist (PT2399). We show that BMAL1-HIF2α is more sensitive than ARNT-HIF2α to suppression by PT2399, and increasing BMAL1 sensitizes 786O cells to growth inhibition by PT2399. Together, these findings indicate that an alternate HIF2α heterodimer containing the circadian partner BMAL1 contributes to HIF2α activity, growth, and sensitivity to HIF2α antagonist drugs in ccRCC cells.

Effect of Urolithin A on the Improvement of Circadian Rhythm Dysregulation in Intestinal Barrier Induced by Inflammation.

Circadian rhythm plays an important role in intestinal homeostasis and intestinal immune function. Circadian rhythm dysregulation was reported to induce intestinal microbiota dysbiosis, intestinal barrier disruption, and trigger intestinal inflammation. However, the relationship between intestinal microbiota metabolites and the circadian rhythm of the intestinal barrier was still unclear. Urolithin A (UA), a kind of intestinal microbial metabolite, was selected in this study. Results showed UA influenced on the expression rhythm of the clock genes BMAL1 and PER2 in intestinal epithelial cells. Furthermore, the study investigated the effects of UA on the expression rhythms of clock genes (BMAL1 and PER2) and tight junctions (OCLN, TJP1, and CLND1), all of which were dysregulated by inflammation. In addition, UA pre-treatment by oral administration to female C57BL/6 mice showed the improvement in the fecal IgA concentrations, tight junction expression (Clnd1 and Clnd4), and clock gene expression (Bmal1 and Per2) in a DSS-induced colitis model induced using DSS treatment. Finally, the Nrf2-SIRT1 signaling pathway was confirmed to be involved in UA's effect on the circadian rhythm of intestinal epithelial cells by antagonist treatment. This study also showed evidence that UA feeding showed an impact on the central clock, which are circadian rhythms in SCN. Therefore, this study highlighted the potential of UA in treating diseases like IBD with sleeping disorders by improving the dysregulated circadian rhythms in both the intestinal barrier and the SCN.

Model integration of circadian- and sleep-wake-driven contributions to rhythmic gene expression reveals distinct regulatory principles

Analyses of gene-expression dynamics in research on circadian rhythms and sleep homeostasis often describe these two processes using separate models. Rhythmically expressed genes are, however, likely to be influenced by both processes. We implemented a driven, damped harmonic oscillator model to estimate the contribution of circadian- and sleep-wake-driven influences on gene expression. The model reliably captured a wide range of dynamics in cortex, liver, and blood transcriptomes taken from mice and humans under various experimental conditions. Sleep-wake-driven factors outweighed circadian factors in driving gene expression in the cortex, whereas the opposite was observed in the liver and blood. Because of tissue- and gene-specific responses, sleep deprivation led to a long-lasting intra- and inter-tissue desynchronization. The model showed that recovery sleep contributed to these long-lasting changes. The results demonstrate that the analyses of the daily rhythms in gene expression must take the complex interactions between circadian and sleep-wake influences into account. A record of this paper's transparent peer review process is included in the supplemental information.