RESUMEN
Transcription-coupled repair (TCR), discovered as preferential nucleotide excision repair of UV-induced cyclobutane pyrimidine dimers located in transcribed mammalian genes compared to those in nontranscribed regions of the genome, is defined as faster repair of the transcribed strand versus the nontranscribed strand in transcribed genes. The phenomenon, universal in model organisms including Escherichia coli, yeast, Arabidopsis, mice, and humans, involves a translocase that interacts with both RNA polymerase stalled at damage in the transcribed strand and nucleotide excision repair proteins to accelerate repair. Drosophila, a notable exception, exhibits TCR but lacks an obvious TCR translocase. Mutations inactivating TCR genes cause increased damage-induced mutagenesis in E. coli and severe neurological and UV sensitivity syndromes in humans. To date, only E. coli TCR has been reconstituted in vitro with purified proteins. Detailed investigations of TCR using genome-wide next-generation sequencing methods, cryo-electron microscopy, single-molecule analysis, and other approaches have revealed fascinating mechanisms.
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Escherichia coli , Transcripción Genética , Humanos , Animales , Ratones , Escherichia coli/genética , Escherichia coli/metabolismo , Microscopía por Crioelectrón , Reparación del ADN , Receptores de Antígenos de Linfocitos T/genética , Receptores de Antígenos de Linfocitos T/metabolismo , Mamíferos/genéticaRESUMEN
Antarctic krill (Euphausia superba) is Earth's most abundant wild animal, and its enormous biomass is vital to the Southern Ocean ecosystem. Here, we report a 48.01-Gb chromosome-level Antarctic krill genome, whose large genome size appears to have resulted from inter-genic transposable element expansions. Our assembly reveals the molecular architecture of the Antarctic krill circadian clock and uncovers expanded gene families associated with molting and energy metabolism, providing insights into adaptations to the cold and highly seasonal Antarctic environment. Population-level genome re-sequencing from four geographical sites around the Antarctic continent reveals no clear population structure but highlights natural selection associated with environmental variables. An apparent drastic reduction in krill population size 10 mya and a subsequent rebound 100 thousand years ago coincides with climate change events. Our findings uncover the genomic basis of Antarctic krill adaptations to the Southern Ocean and provide valuable resources for future Antarctic research.
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Euphausiacea , Genoma , Animales , Relojes Circadianos/genética , Ecosistema , Euphausiacea/genética , Euphausiacea/fisiología , Genómica , Análisis de Secuencia de ADN , Elementos Transponibles de ADN , Evolución Biológica , Adaptación FisiológicaRESUMEN
The prevalence of type 2 diabetes and obesity has risen dramatically for decades and is expected to rise further, secondary to the growing aging, sedentary population. The strain on global health care is projected to be colossal. This review explores the latest work and emerging ideas related to genetic and environmental factors influencing metabolism. Translational research and clinical applications, including the impact of the COVID-19 pandemic, are highlighted. Looking forward, strategies to personalize all aspects of prevention, management and care are necessary to improve health outcomes and reduce the impact of these metabolic diseases.
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COVID-19/epidemiología , Diabetes Mellitus Tipo 2/epidemiología , Diabetes Mellitus Tipo 2/terapia , Obesidad/epidemiología , Obesidad/terapia , Pandemias , Medicina de Precisión/métodos , SARS-CoV-2 , COVID-19/virología , Ritmo Circadiano , Diabetes Mellitus Tipo 2/genética , Diabetes Mellitus Tipo 2/metabolismo , Epigénesis Genética , Predisposición Genética a la Enfermedad , Humanos , Inflamación/inmunología , Inflamación/metabolismo , Obesidad/genética , Obesidad/metabolismo , Prevalencia , Factores de Riesgo , TermotoleranciaRESUMEN
Environmental light cycles entrain circadian feeding behaviors in animals that produce rhythms in exposure to foodborne bacteria. Here, we show that the intestinal microbiota generates diurnal rhythms in innate immunity that synchronize with feeding rhythms to anticipate microbial exposure. Rhythmic expression of antimicrobial proteins was driven by daily rhythms in epithelial attachment by segmented filamentous bacteria (SFB), members of the mouse intestinal microbiota. Rhythmic SFB attachment was driven by the circadian clock through control of feeding rhythms. Mechanistically, rhythmic SFB attachment activated an immunological circuit involving group 3 innate lymphoid cells. This circuit triggered oscillations in epithelial STAT3 expression and activation that produced rhythmic antimicrobial protein expression and caused resistance to Salmonella Typhimurium infection to vary across the day-night cycle. Thus, host feeding rhythms synchronize with the microbiota to promote rhythms in intestinal innate immunity that anticipate exogenous microbial exposure.
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Relojes Circadianos/fisiología , Ritmo Circadiano/fisiología , Microbioma Gastrointestinal , Inmunidad Innata , Animales , Péptidos Catiónicos Antimicrobianos/metabolismo , Adhesión Bacteriana , Adhesión Celular , Células Epiteliales/microbiología , Conducta Alimentaria , Intestino Delgado/microbiología , Intestino Delgado/ultraestructura , Linfocitos/metabolismo , Ratones Endogámicos C57BL , Muramidasa/metabolismo , Proteínas Asociadas a Pancreatitis/metabolismo , Factor de Transcripción STAT3/metabolismo , Salmonelosis Animal/microbiología , Transducción de SeñalRESUMEN
Throughout a 24-h period, the small intestine (SI) is exposed to diurnally varying food- and microbiome-derived antigenic burdens but maintains a strict immune homeostasis, which when perturbed in genetically susceptible individuals, may lead to Crohn disease. Herein, we demonstrate that dietary content and rhythmicity regulate the diurnally shifting SI epithelial cell (SIEC) transcriptional landscape through modulation of the SI microbiome. We exemplify this concept with SIEC major histocompatibility complex (MHC) class II, which is diurnally modulated by distinct mucosal-adherent SI commensals, while supporting downstream diurnal activity of intra-epithelial IL-10+ lymphocytes regulating the SI barrier function. Disruption of this diurnally regulated diet-microbiome-MHC class II-IL-10-epithelial barrier axis by circadian clock disarrangement, alterations in feeding time or content, or epithelial-specific MHC class II depletion leads to an extensive microbial product influx, driving Crohn-like enteritis. Collectively, we highlight nutritional features that modulate SI microbiome, immunity, and barrier function and identify dietary, epithelial, and immune checkpoints along this axis to be potentially exploitable in future Crohn disease interventions.
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Enfermedad de Crohn/microbiología , Células Epiteliales/metabolismo , Microbioma Gastrointestinal , Antígenos de Histocompatibilidad Clase II/metabolismo , Intestino Delgado/inmunología , Intestino Delgado/microbiología , Transcriptoma/genética , Animales , Antibacterianos/farmacología , Relojes Circadianos/fisiología , Enfermedad de Crohn/inmunología , Enfermedad de Crohn/metabolismo , Dieta , Células Epiteliales/citología , Células Epiteliales/inmunología , Citometría de Flujo , Microbioma Gastrointestinal/efectos de los fármacos , Microbioma Gastrointestinal/genética , Perfilación de la Expresión Génica , Antígenos de Histocompatibilidad Clase II/genética , Homeostasis , Hibridación Fluorescente in Situ , Interleucina-10/metabolismo , Interleucina-10/farmacología , Intestino Delgado/fisiología , Linfocitos , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Periodicidad , Linfocitos T/inmunología , Transcriptoma/fisiologíaRESUMEN
Neurons use two main schemes to encode information: rate coding (frequency of firing) and temporal coding (timing or pattern of firing). While the importance of rate coding is well established, it remains controversial whether temporal codes alone are sufficient for controlling behavior. Moreover, the molecular mechanisms underlying the generation of specific temporal codes are enigmatic. Here, we show in Drosophila clock neurons that distinct temporal spike patterns, dissociated from changes in firing rate, encode time-dependent arousal and regulate sleep. From a large-scale genetic screen, we identify the molecular pathways mediating the circadian-dependent changes in ionic flux and spike morphology that rhythmically modulate spike timing. Remarkably, the daytime spiking pattern alone is sufficient to drive plasticity in downstream arousal neurons, leading to increased firing of these cells. These findings demonstrate a causal role for temporal coding in behavior and define a form of synaptic plasticity triggered solely by temporal spike patterns.
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Plasticidad Neuronal , Sueño/fisiología , Potenciales de Acción , Animales , Relojes Circadianos/fisiología , Drosophila , Proteínas de Drosophila/antagonistas & inhibidores , Proteínas de Drosophila/genética , Proteínas de Drosophila/metabolismo , Modelos Neurológicos , Neuronas/metabolismo , Optogenética , Canales de Potasio/genética , Canales de Potasio/metabolismo , Canales de Potasio Calcio-Activados/metabolismo , Interferencia de ARN , ARN Interferente Pequeño/metabolismo , Receptores de N-Metil-D-Aspartato/metabolismo , Transducción de Señal , ATPasa Intercambiadora de Sodio-Potasio/antagonistas & inhibidores , ATPasa Intercambiadora de Sodio-Potasio/genética , ATPasa Intercambiadora de Sodio-Potasio/metabolismo , Transmisión SinápticaRESUMEN
Patterns of daily human activity are controlled by an intrinsic circadian clock that promotes â¼24 hr rhythms in many behavioral and physiological processes. This system is altered in delayed sleep phase disorder (DSPD), a common form of insomnia in which sleep episodes are shifted to later times misaligned with the societal norm. Here, we report a hereditary form of DSPD associated with a dominant coding variation in the core circadian clock gene CRY1, which creates a transcriptional inhibitor with enhanced affinity for circadian activator proteins Clock and Bmal1. This gain-of-function CRY1 variant causes reduced expression of key transcriptional targets and lengthens the period of circadian molecular rhythms, providing a mechanistic link to DSPD symptoms. The allele has a frequency of up to 0.6%, and reverse phenotyping of unrelated families corroborates late and/or fragmented sleep patterns in carriers, suggesting that it affects sleep behavior in a sizeable portion of the human population.
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Criptocromos/metabolismo , Trastornos del Sueño del Ritmo Circadiano/genética , Ritmo Circadiano , Criptocromos/genética , Exones , Femenino , Eliminación de Gen , Humanos , Masculino , Persona de Mediana Edad , Linaje , Trastornos del Sueño del Ritmo Circadiano/fisiopatologíaRESUMEN
The process of aging and circadian rhythms are intimately intertwined, but how peripheral clocks involved in metabolic homeostasis contribute to aging remains unknown. Importantly, caloric restriction (CR) extends lifespan in several organisms and rewires circadian metabolism. Using young versus old mice, fed ad libitum or under CR, we reveal reprogramming of the circadian transcriptome in the liver. These age-dependent changes occur in a highly tissue-specific manner, as demonstrated by comparing circadian gene expression in the liver versus epidermal and skeletal muscle stem cells. Moreover, de novo oscillating genes under CR show an enrichment in SIRT1 targets in the liver. This is accompanied by distinct circadian hepatic signatures in NAD+-related metabolites and cyclic global protein acetylation. Strikingly, this oscillation in acetylation is absent in old mice while CR robustly rescues global protein acetylation. Our findings indicate that the clock operates at the crossroad between protein acetylation, liver metabolism, and aging.
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Envejecimiento/metabolismo , Ritmo Circadiano , Hígado/metabolismo , Redes y Vías Metabólicas , Acetilcoenzima A/metabolismo , Acetilación , Envejecimiento/patología , Animales , Restricción Calórica , Histonas/metabolismo , Hígado/patología , Ratones , NAD/metabolismo , Proteínas/metabolismo , Sirtuina 1/metabolismo , Células Madre/metabolismo , TranscriptomaRESUMEN
This review explores the interface between circadian timekeeping and the regulation of brain function by astrocytes. Although astrocytes regulate neuronal activity across many time domains, their cell-autonomous circadian clocks exert a particular role in controlling longer-term oscillations of brain function: the maintenance of sleep states and the circadian ordering of sleep and wakefulness. This is most evident in the central circadian pacemaker, the suprachiasmatic nucleus, where the molecular clock of astrocytes suffices to drive daily cycles of neuronal activity and behavior. In Alzheimer's disease, sleep impairments accompany cognitive decline. In mouse models of the disease, circadian disturbances accelerate astroglial activation and other brain pathologies, suggesting that daily functions in astrocytes protect neuronal homeostasis. In brain cancer, treatment in the morning has been associated with prolonged survival, and gliomas have daily rhythms in gene expression and drug sensitivity. Thus, circadian time is fast becoming critical to elucidating reciprocal astrocytic-neuronal interactions in health and disease.
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Astrocitos , Relojes Circadianos , Ratones , Animales , Astrocitos/fisiología , Ritmo Circadiano/fisiología , Relojes Circadianos/genética , Sueño , Núcleo Supraquiasmático/metabolismoRESUMEN
The intestinal microbiota undergoes diurnal compositional and functional oscillations that affect metabolic homeostasis, but the mechanisms by which the rhythmic microbiota influences host circadian activity remain elusive. Using integrated multi-omics and imaging approaches, we demonstrate that the gut microbiota features oscillating biogeographical localization and metabolome patterns that determine the rhythmic exposure of the intestinal epithelium to different bacterial species and their metabolites over the course of a day. This diurnal microbial behavior drives, in turn, the global programming of the host circadian transcriptional, epigenetic, and metabolite oscillations. Surprisingly, disruption of homeostatic microbiome rhythmicity not only abrogates normal chromatin and transcriptional oscillations of the host, but also incites genome-wide de novo oscillations in both intestine and liver, thereby impacting diurnal fluctuations of host physiology and disease susceptibility. As such, the rhythmic biogeography and metabolome of the intestinal microbiota regulates the temporal organization and functional outcome of host transcriptional and epigenetic programs.
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Ritmo Circadiano , Colon/microbiología , Microbioma Gastrointestinal , Transcriptoma , Animales , Cromatina/metabolismo , Colon/metabolismo , Vida Libre de Gérmenes , Hígado/metabolismo , Ratones , Microscopía Electrónica de RastreoRESUMEN
The circadian clock plays an essential role in coordinating feeding and metabolic rhythms with the light/dark cycle. Disruption of clocks is associated with increased adiposity and metabolic disorders, whereas aligning feeding time with cell-autonomous rhythms in metabolism improves health. Here, we provide a comprehensive overview of recent literature in adipose tissue biology as well as our understanding of molecular mechanisms underlying the circadian regulation of transcription, metabolism, and inflammation in adipose tissue. We highlight recent efforts to uncover the mechanistic links between clocks and adipocyte metabolism, as well as its application to dietary and behavioral interventions to improve health and mitigate obesity.
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Tejido Adiposo , Relojes Circadianos , Humanos , Tejido Adiposo/fisiología , Relojes Circadianos/genética , Obesidad , Ritmo Circadiano/genética , Metabolismo EnergéticoRESUMEN
In all organisms with circadian clocks, post-translational modifications of clock proteins control the dynamics of circadian rhythms, with phosphorylation playing a dominant role. All major clock proteins are highly phosphorylated, and many kinases have been described to be responsible. In contrast, it is largely unclear whether and to what extent their counterparts, the phosphatases, play an equally crucial role. To investigate this, we performed a systematic RNAi screen in human cells and identified protein phosphatase 4 (PPP4) with its regulatory subunit PPP4R2 as critical components of the circadian system in both mammals and Drosophila Genetic depletion of PPP4 shortens the circadian period, whereas overexpression lengthens it. PPP4 inhibits CLOCK/BMAL1 transactivation activity by binding to BMAL1 and counteracting its phosphorylation. This leads to increased CLOCK/BMAL1 DNA occupancy and decreased transcriptional activity, which counteracts the "kamikaze" properties of CLOCK/BMAL1. Through this mechanism, PPP4 contributes to the critical delay of negative feedback by retarding PER/CRY/CK1δ-mediated inhibition of CLOCK/BMAL1.
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Relojes Circadianos , Factores de Transcripción ARNTL/genética , Factores de Transcripción ARNTL/metabolismo , Animales , Proteínas CLOCK/genética , Proteínas CLOCK/metabolismo , Relojes Circadianos/genética , Ritmo Circadiano/genética , Criptocromos/genética , Mamíferos , Fosfoproteínas FosfatasasRESUMEN
In mammals, virtually all body cells harbor cell-autonomous and self-sustained circadian oscillators that rely on delayed negative feedback loops in gene expression. Transcriptional activation and repression play a major role in keeping these clocks ticking, but numerous post-translational mechanisms-and particularly the phosphorylation of core clock components by protein kinases-are also critically involved in setting the pace of these timekeepers. In this issue of Genes & Development, Klemz and colleagues (pp. 1161-1174) now show how dephosphorylation of BMAL1 by protein phosphatase 4 (PPP4) participates in the modulation of circadian timing.
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Relojes Circadianos , Factores de Transcripción ARNTL/genética , Factores de Transcripción ARNTL/metabolismo , Animales , Proteínas CLOCK/genética , Proteínas CLOCK/metabolismo , Relojes Circadianos/genética , Ritmo Circadiano/genética , Mamíferos , Fosforilación , Procesamiento Proteico-PostraduccionalRESUMEN
Neutrophils eliminate pathogens efficiently but can inflict severe damage to the host if they over-activate within blood vessels. It is unclear how immunity solves the dilemma of mounting an efficient anti-microbial defense while preserving vascular health. Here, we identify a neutrophil-intrinsic program that enabled both. The gene Bmal1 regulated expression of the chemokine CXCL2 to induce chemokine receptor CXCR2-dependent diurnal changes in the transcriptional and migratory properties of circulating neutrophils. These diurnal alterations, referred to as neutrophil aging, were antagonized by CXCR4 (C-X-C chemokine receptor type 4) and regulated the outer topology of neutrophils to favor homeostatic egress from blood vessels at night, resulting in boosted anti-microbial activity in tissues. Mice engineered for constitutive neutrophil aging became resistant to infection, but the persistence of intravascular aged neutrophils predisposed them to thrombo-inflammation and death. Thus, diurnal compartmentalization of neutrophils, driven by an internal timer, coordinates immune defense and vascular protection.
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Vasos Sanguíneos/inmunología , Ritmo Circadiano/inmunología , Neutrófilos/inmunología , Fagocitosis/inmunología , Animales , Vasos Sanguíneos/metabolismo , Candida albicans/inmunología , Candida albicans/fisiología , Células Cultivadas , Senescencia Celular/inmunología , Quimiocina CXCL2/inmunología , Quimiocina CXCL2/metabolismo , Interacciones Huésped-Patógeno/inmunología , Humanos , Inflamación/inmunología , Inflamación/metabolismo , Masculino , Ratones Endogámicos C57BL , Ratones Noqueados , Infiltración Neutrófila/inmunología , Neutrófilos/metabolismo , Neutrófilos/microbiología , Receptores CXCR4/inmunología , Receptores CXCR4/metabolismo , Factores de TiempoRESUMEN
The circadian clock is encoded by a negative transcriptional feedback loop that coordinates physiology and behavior through molecular programs that remain incompletely understood. Here, we reveal rhythmic genome-wide alternative splicing (AS) of pre-mRNAs encoding regulators of peptidergic secretion within pancreatic ß cells that are perturbed in Clock-/- and Bmal1-/- ß-cell lines. We show that the RNA-binding protein THRAP3 (thyroid hormone receptor-associated protein 3) regulates circadian clock-dependent AS by binding to exons at coding sequences flanking exons that are more frequently skipped in clock mutant ß cells, including transcripts encoding Cask (calcium/calmodulin-dependent serine protein kinase) and Madd (MAP kinase-activating death domain). Depletion of THRAP3 restores expression of the long isoforms of Cask and Madd, and mimicking exon skipping in these transcripts through antisense oligonucleotide delivery in wild-type islets reduces glucose-stimulated insulin secretion. Finally, we identify shared networks of alternatively spliced exocytic genes from islets of rodent models of diet-induced obesity that significantly overlap with clock mutants. Our results establish a role for pre-mRNA alternative splicing in ß-cell function across the sleep/wake cycle.
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Empalme Alternativo , Relojes Circadianos/genética , Exocitosis , Glucosa/metabolismo , Secreción de Insulina/genética , Factores de Transcripción ARNTL/genética , Factores de Transcripción ARNTL/fisiología , Animales , Proteínas CLOCK/genética , Proteínas CLOCK/fisiología , Células Cultivadas , Proteínas Adaptadoras de Señalización del Receptor del Dominio de Muerte/genética , Proteínas Adaptadoras de Señalización del Receptor del Dominio de Muerte/metabolismo , Factores de Intercambio de Guanina Nucleótido/genética , Factores de Intercambio de Guanina Nucleótido/metabolismo , Guanilato-Quinasas/genética , Guanilato-Quinasas/metabolismo , Homeostasis , Células Secretoras de Insulina/metabolismo , Islotes Pancreáticos/metabolismo , Masculino , Ratones Endogámicos C57BL , Proteínas Nucleares/fisiología , Obesidad/genética , Obesidad/metabolismo , Proteína 25 Asociada a Sinaptosomas/genética , Proteína 25 Asociada a Sinaptosomas/metabolismo , Factores de Transcripción/fisiologíaRESUMEN
The glucocorticoid receptor (GR) is a potent metabolic regulator and a major drug target. While GR is known to play integral roles in circadian biology, its rhythmic genomic actions have never been characterized. Here we mapped GR's chromatin occupancy in mouse livers throughout the day and night cycle. We show how GR partitions metabolic processes by time-dependent target gene regulation and controls circulating glucose and triglycerides differentially during feeding and fasting. Highlighting the dominant role GR plays in synchronizing circadian amplitudes, we find that the majority of oscillating genes are bound by and depend on GR. This rhythmic pattern is altered by high-fat diet in a ligand-independent manner. We find that the remodeling of oscillatory gene expression and postprandial GR binding results from a concomitant increase of STAT5 co-occupancy in obese mice. Altogether, our findings highlight GR's fundamental role in the rhythmic orchestration of hepatic metabolism.
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Cromatina/metabolismo , Relojes Circadianos , Ritmo Circadiano , Dieta Alta en Grasa , Grasas de la Dieta/metabolismo , Metabolismo Energético , Hígado/metabolismo , Obesidad/metabolismo , Receptores de Glucocorticoides/metabolismo , Animales , Glucemia/metabolismo , Relojes Circadianos/genética , Ritmo Circadiano/genética , Grasas de la Dieta/administración & dosificación , Grasas de la Dieta/sangre , Modelos Animales de Enfermedad , Metabolismo Energético/genética , Ayuno/metabolismo , Regulación de la Expresión Génica , Glucocorticoides/metabolismo , Gluconeogénesis , Ligandos , Masculino , Ratones Endogámicos C57BL , Ratones Noqueados , Obesidad/sangre , Obesidad/genética , PPAR alfa/genética , PPAR alfa/metabolismo , Periodo Posprandial , Receptores de Glucocorticoides/deficiencia , Receptores de Glucocorticoides/genética , Factor de Transcripción STAT5/genética , Factor de Transcripción STAT5/metabolismo , Vías Secretoras , Transducción de Señal , Factores de Tiempo , Transcripción Genética , Triglicéridos/sangreRESUMEN
One important goal of circadian medicine is to apply time-of-day dosing to improve the efficacy of chemotherapy. However, limited knowledge of how the circadian clock regulates DNA repair presents a challenge to mechanism-based clinical application. We studied time-series genome-wide nucleotide excision repair in liver and kidney of wild type and three different clock mutant genotypes (Cry1-/-Cry2-/-, Per1-/-Per2-/-, and Bmal1-/-). Rhythmic repair on the nontranscribed strand was lost in all three clock mutants. Conversely, rhythmic repair of hundreds of genes on the transcribed strand (TSs) persisted in the livers of Cry1-/-Cry2-/- and Per1-/-Per2-/- mice. We identified a tissue-specific, promoter element-driven repair mode on TSs of collagen and angiogenesis genes in the absence of clock activators or repressors. Furthermore, repair on TSs of thousands of genes was altered when the circadian clock is disrupted. These data contribute to a better understanding of the regulatory role of the circadian clock on nucleotide excision repair in mammals and may be invaluable toward the design of time-aware platinum-based interventions in cancer.
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Relojes Circadianos , Animales , Ratones , Relojes Circadianos/genética , Ritmo Circadiano/genética , Proteínas CLOCK/genética , Mutación , Nucleótidos , Criptocromos/genética , Factores de Transcripción ARNTL/genética , MamíferosRESUMEN
Time-restricted feeding (RF) is known to shift the phasing of gene expression in most primary metabolic tissues, whereas a time misalignment between the suprachiasmatic nucleus circadian clock (SCNCC) and its peripheral CCs (PCC's) is known to induce various pathophysiological conditions, including a metabolic syndrome. We now report that a unique "light therapy," involving different light intensities (TZT0-ZT12150-TZT0-ZT12700 lx, TZT0-ZT1275-TZT0-ZT12150 lx, and TZT0-ZT12350-TZT0-ZT12700 lx), realigns the RF-generated misalignment between the SCNCC and the PCC's. Using such high-light regime, we show that through shifting the SCNCC and its activity, it is possible in a RF and "night-shifted mouse model" to prevent/correct pathophysiologies (e.g., a metabolic syndrome, a loss of memory, cardiovascular abnormalities). Our data indicate that such a "high-light regime" could be used as a unique chronotherapy, for those working on night shifts or suffering from jet-lag, in order to realign their SCNCC and PCC's, thereby preventing the generation of pathophysiological conditions.
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Relojes Circadianos , Núcleo Supraquiasmático , Animales , Relojes Circadianos/fisiología , Ratones , Núcleo Supraquiasmático/metabolismo , Síndrome Metabólico/terapia , Síndrome Metabólico/metabolismo , Fototerapia/métodos , Masculino , Ratones Endogámicos C57BL , Ritmo Circadiano/fisiología , LuzRESUMEN
Climate change is a global concern for all life on our planet, including humans and plants. Plants' growth and development are significantly affected by abiotic stresses, including adverse temperature, inadequate or excess water availability, nutrient deficiency, and salinity. The circadian clock is a master regulator of numerous developmental and metabolic processes in plants. In an effort to identify new clock-related genes and outputs through bioinformatic analysis, we have revealed that CIRCADIAN CLOCK ASSOCIATED 1 (CCA1) and LATE ELONGATED HYPOCOTYL (LHY) play a crucial role in regulating a wide range of abiotic stress responses and target ABSCISIC ACID RESPONSIVE ELEMENTS-BINDING FACTOR3 (ABF3), a key transcription factor in the plant hormone Abscisic acid (ABA)-signaling pathway. Specifically, we found that CCA1 and LHY regulate the expression of ABF3 under diel conditions, as well as seed germination under salinity. Conversely, ABF3 controls the expression of core clock genes and orchestrates the circadian period in a stress-responsive manner. ABF3 delivers the stress signal to the central oscillator by binding to the promoter of CCA1 and LHY. Overall, our study uncovers the reciprocal regulation between ABF3 and CCA1/LHY and molecular mechanisms underlying the interaction between the circadian clock and abiotic stress. This finding may aid in developing molecular and genetic solutions for plants to survive and thrive in the face of climate change.
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Proteínas de Arabidopsis , Arabidopsis , Relojes Circadianos , Humanos , Relojes Circadianos/genética , Proteínas de Unión al ADN/metabolismo , Proteínas de Arabidopsis/metabolismo , Arabidopsis/genética , Ácido Abscísico/metabolismo , Ritmo Circadiano/genética , Regulación de la Expresión Génica de las Plantas , Estrés Fisiológico , Factores de Transcripción/metabolismoRESUMEN
The circadian clock in the suprachiasmatic nucleus (SCN) of mammals drives 24-h rhythms of sleep/wake cycles. Peripheral clocks present in other organs coordinate local and global physiology according to rhythmic signals from the SCN and via metabolic cues. The core circadian clockwork is identical in all cells. However, there is only a small amount of overlap of the circadian transcriptomes in different organs and tissues. A novel study by Beytebiere and colleagues (pp. 294-309) indicates that the regulation of tissue-specific rhythmic gene expression involves the cooperation of the circadian transcription factor (TF) BMAL1:CLOCK with tissue-specific TFs (ts-TFs) and correlates with the potential of BMAL1:CLOCK to facilitate rhythmic enhancer-enhancer interactions.