bims-ciryme Biomed News
on Circadian rhythms and metabolism
Issue of 2023–09–03
seven papers selected by
Gabriela Da Silva Xavier, University of Birmingham
  1. Endogenous circadian rhythms in mood and well-being.
  2. Circadian Regulation of Liver Energy Metabolism: Experimental Approaches in Human, Rodent and Cellular Models.
  3. Clock-dependent chromatin accessibility rhythms regulate circadian transcription.
  4. In vivo recording of suprachiasmatic nucleus dynamics reveals a dominant role of arginine vasopressin neurons in circadian pacesetting.
  5. Integrated multi-omics analysis reveals the molecular interplay between circadian clocks and cancer pathogenesis.
  6. MYC disrupts transcriptional and metabolic circadian oscillations in cancer and promotes enhanced biosynthesis.
  7. Objective and subjective measures of sleep initiation are differentially associated with DNA methylation in adolescents.
  1. Sleep Health. 2023 Aug 28. pii: S2352-7218(23)00162-6. [Epub ahead of print]
    Endogenous circadian rhythms in mood and well-being.
    Frank A J L Scheer, Sarah L Chellappa.
       OBJECTIVES: We examined whether the endogenous circadian timing system modulates proxies of mood vulnerability and well-being.
    METHODS: Nineteen healthy participants (mean age: 26.6 years [23.0-30.2], seven females, body-mass index: 22.8 kg/m2 [21.1-25]) completed a laboratory protocol with a 32-hour Constant Routine, a stringently controlled protocol designed to isolate assessment of endogenous circadian rhythms. We assessed hourly anxiety- and depression-like mood (i.e., those typically observed in depression and anxiety) and well-being (i.e., associated with mental fatigue and physical comfort).
    RESULTS: Significant endogenous circadian rhythms were observed in anxiety-like and depression-like mood, as well as well-being (p values from the mixed-model analysis using false discovery rates < .001). Post-hoc comparisons revealed more anxiety-like and depression-like mood during the circadian phase 60°-75° (∼8-9 a.m.), and more mental fatigue and less physical comfort during the circadian phase 30°-60° (∼6-8 a.m.).
    CONCLUSIONS: Our data indicate endogenous circadian rhythms in anxiety-like and depression-like mood and well-being in healthy young adults. Future studies will help establish circadian-based therapeutics for individuals experiencing mood and anxiety disorders.
    Keywords:  Circadian rhythms; Emotional regulation; Mental health; Mood vulnerability; Sleep
    DOI:  https://doi.org/10.1016/j.sleh.2023.07.012
  2. Am J Physiol Cell Physiol. 2023 Aug 29.
    Circadian Regulation of Liver Energy Metabolism: Experimental Approaches in Human, Rodent and Cellular Models.
    Lorna J Daniels, Danielle Kay, Thomas Marjot, Leanne Hodson, David W Ray.
      Circadian rhythms are endogenous oscillations with approximately 24 hour period that allow organisms to anticipate the change between day and night. Disruptions that desynchronise or misalign circadian rhythms are associated with an increased risk of cardiometabolic disease. This review focuses on the liver circadian clock as relevant to the risk of developing metabolic diseases including NAFLD, insulin resistance and type 2 diabetes. Many liver functions exhibit rhythmicity. Approximately ~40% of the hepatic transcriptome exhibit 24 hour rhythms, along with rhythms in protein levels, post-translational modification, and various metabolites. The liver circadian clock is critical for maintaining glucose and lipid homeostasis. Most of the attention in the metabolic field has been directed towards diet, exercise, and rather little to modifiable risks due to circadian misalignment or disruption. Therefore, the aim of this review is to systematically analyse the various approaches to the circadian liver, targeting metabolic liver diseases, using human, rodent and cell biology models.
    Keywords:  Circadian; Glucose; Lipids; Misalignment; Shift work
    DOI:  https://doi.org/10.1152/ajpcell.00551.2022
  3. bioRxiv. 2023 Aug 16. pii: 2023.08.15.553315. [Epub ahead of print]
    Clock-dependent chromatin accessibility rhythms regulate circadian transcription.
    Ye Yuan, Qianqian Chen, Margarita Brovkina, E Josephine Clowney, Swathi Yadlapalli.
      Chromatin organization plays a crucial role in gene regulation by controlling the accessibility of DNA to transcription machinery. While significant progress has been made in understanding the regulatory role of clock proteins in circadian rhythms, how chromatin organization affects circadian rhythms remains poorly understood. Here, we employed ATAC-seq (Assay for Transposase-Accessible Chromatin with Sequencing) on FAC-sorted Drosophila clock neurons to assess genome-wide chromatin accessibility over the circadian cycle. We observed significant circadian oscillations in chromatin accessibility at promoter and enhancer regions of hundreds of genes, with enhanced accessibility either at dusk or dawn, which correlated with their peak transcriptional activity. Notably, genes with enhanced accessibility at dusk were enriched with E-box motifs, while those more accessible at dawn were enriched with VRI/PDP1-box motifs, indicating that they are regulated by the core circadian feedback loops, PER/CLK and VRI/PDP1, respectively. Further, we observed a complete loss of chromatin accessibility rhythms in per 01 null mutants, with chromatin consistently accessible throughout the circadian cycle, underscoring the critical role of Period protein in driving chromatin compaction during the repression phase. Together, this study demonstrates the significant role of chromatin organization in circadian regulation, revealing how the interplay between clock proteins and chromatin structure orchestrates the precise timing of biological processes throughout the day. This work further implies that variations in chromatin accessibility might play a central role in the generation of diverse circadian gene expression patterns in clock neurons.
    Significance Statement: Chromatin organization plays a critical role in gene regulation in development and in disease. In this study, we discovered robust circadian oscillations in the chromatin accessibility of regulatory elements of clock-regulated genes in Drosophila clock neurons, with enhanced accessibility either at dusk or dawn, which correlated with their peak transcriptional activity. We found enrichment of E-box motifs in genes that exhibited enhanced accessibility at dusk, and enrichment of VRI/PDP1-box motifs in genes that exhibited higher accessibility at dawn. Moreover, the complete loss of chromatin accessibility rhythms in per 01 mutants highlights the essential role of the Period protein in driving chromatin compaction during the repression phase. This study highlights the significance of chromatin organization in the generation of ∼24-hour circadian rhythms.
    DOI:  https://doi.org/10.1101/2023.08.15.553315
  4. PLoS Biol. 2023 Aug;21(8): e3002281
    In vivo recording of suprachiasmatic nucleus dynamics reveals a dominant role of arginine vasopressin neurons in circadian pacesetting.
    Yusuke Tsuno, Yubo Peng, Shin-Ichi Horike, Mohan Wang, Ayako Matsui, Kanato Yamagata, Mizuki Sugiyama, Takahiro J Nakamura, Takiko Daikoku, Takashi Maejima, Michihiro Mieda.
      The central circadian clock of the suprachiasmatic nucleus (SCN) is a network consisting of various types of neurons and glial cells. Individual cells have the autonomous molecular machinery of a cellular clock, but their intrinsic periods vary considerably. Here, we show that arginine vasopressin (AVP) neurons set the ensemble period of the SCN network in vivo to control the circadian behavior rhythm. Artificial lengthening of cellular periods by deleting casein kinase 1 delta (CK1δ) in the whole SCN lengthened the free-running period of behavior rhythm to an extent similar to CK1δ deletion specific to AVP neurons. However, in SCN slices, PER2::LUC reporter rhythms of these mice only partially and transiently recapitulated the period lengthening, showing a dissociation between the SCN shell and core with a period instability in the shell. In contrast, in vivo calcium rhythms of both AVP and vasoactive intestinal peptide (VIP) neurons in the SCN of freely moving mice demonstrated stably lengthened periods similar to the behavioral rhythm upon AVP neuron-specific CK1δ deletion, without changing the phase relationships between each other. Furthermore, optogenetic activation of AVP neurons acutely induced calcium increase in VIP neurons in vivo. These results indicate that AVP neurons regulate other SCN neurons, such as VIP neurons, in vivo and thus act as a primary determinant of the SCN ensemble period.
    DOI:  https://doi.org/10.1371/journal.pbio.3002281
  5. Sci Rep. 2023 08 30. 13(1): 14198
    Integrated multi-omics analysis reveals the molecular interplay between circadian clocks and cancer pathogenesis.
    Andy Pérez-Villa, Gabriela Echeverría-Garcés, María José Ramos-Medina, Lavanya Prathap, Mayra Martínez-López, David Ramírez-Sánchez, Jennyfer M García-Cárdenas, Isaac Armendáriz-Castillo, Santiago Guerrero, Clara Paz, Andrés López-Cortés.
      Circadian rhythms (CRs) are fundamental biological processes that significantly impact human well-being. Disruption of these rhythms can trigger insufficient neurocognitive development, insomnia, mental disorders, cardiovascular diseases, metabolic dysfunctions, and cancer. The field of chronobiology has increased our understanding of how rhythm disturbances contribute to cancer pathogenesis, and how circadian timing influences the efficacy of cancer treatments. As the circadian clock steadily gains recognition as an emerging factor in tumorigenesis, a thorough and comprehensive multi-omics analysis of CR genes/proteins has never been performed. To shed light on this, we performed, for the first time, an integrated data analysis encompassing genomic/transcriptomic alterations across 32 cancer types (n = 10,918 tumors) taken from the PanCancer Atlas, unfavorable prognostic protein analysis, protein-protein interactomics, and shortest distance score pathways to cancer hallmark phenotypes. This data mining strategy allowed us to unravel 31 essential CR-related proteins involved in the signaling crossroad between circadian rhythms and cancer. In the context of drugging the clock, we identified pharmacogenomic clinical annotations and drugs currently in late phase clinical trials that could be considered as potential cancer therapeutic strategies. These findings highlight the diverse roles of CR-related genes/proteins in the realm of cancer research and therapy.
    DOI:  https://doi.org/10.1038/s41598-023-39401-1
  6. PLoS Genet. 2023 Aug 28. 19(8): e1010904
    MYC disrupts transcriptional and metabolic circadian oscillations in cancer and promotes enhanced biosynthesis.
    Juliana Cazarin, Rachel E DeRollo, Siti Noor Ain Binti Ahmad Shahidan, Jamison B Burchett, Daniel Mwangi, Saikumari Krishnaiah, Annie L Hsieh, Zandra E Walton, Rebekah Brooks, Stephano S Mello, Aalim M Weljie, Chi V Dang, Brian J Altman.
      The molecular circadian clock, which controls rhythmic 24-hour oscillation of genes, proteins, and metabolites in healthy tissues, is disrupted across many human cancers. Deregulated expression of the MYC oncoprotein has been shown to alter expression of molecular clock genes, leading to a disruption of molecular clock oscillation across cancer types. It remains unclear what benefit cancer cells gain from suppressing clock oscillation, and how this loss of molecular clock oscillation impacts global gene expression and metabolism in cancer. We hypothesized that MYC or its paralog N-MYC (collectively termed MYC herein) suppress oscillation of gene expression and metabolism to upregulate pathways involved in biosynthesis in a static, non-oscillatory fashion. To test this, cells from distinct cancer types with inducible MYC were examined, using time-series RNA-sequencing and metabolomics, to determine the extent to which MYC activation disrupts global oscillation of genes, gene expression pathways, and metabolites. We focused our analyses on genes, pathways, and metabolites that changed in common across multiple cancer cell line models. We report here that MYC disrupted over 85% of oscillating genes, while instead promoting enhanced ribosomal and mitochondrial biogenesis and suppressed cell attachment pathways. Notably, when MYC is activated, biosynthetic programs that were formerly circadian flipped to being upregulated in an oscillation-free manner. Further, activation of MYC ablates the oscillation of nutrient transporter proteins while greatly upregulating transporter expression, cell surface localization, and intracellular amino acid pools. Finally, we report that MYC disrupts metabolite oscillations and the temporal segregation of amino acid metabolism from nucleotide metabolism. Our results demonstrate that MYC disruption of the molecular circadian clock releases metabolic and biosynthetic processes from circadian control, which may provide a distinct advantage to cancer cells.
    DOI:  https://doi.org/10.1371/journal.pgen.1010904
  7. Clin Epigenetics. 2023 08 26. 15(1): 136
    Objective and subjective measures of sleep initiation are differentially associated with DNA methylation in adolescents.
    Michael Larsen, Fan He, Yuka Imamura Kawasawa, Arthur Berg, Alexandros N Vgontzas, Duanping Liao, Edward O Bixler, Julio Fernandez-Mendoza.
       INTRODUCTION: The onset of puberty is associated with a shift in the circadian timing of sleep, leading to delayed sleep initiation [i.e., later sleep onset time (SOT)] due to later bedtimes and/or longer sleep onset latency (SOL). Several genome-wide association studies (GWAS) have identified genes that may be involved in the etiology of sleep phenotypes. However, circadian rhythms are also epigenetically regulated; therefore, epigenetic biomarkers may provide insight into the physiology of the pubertal sleep onset shift and the pathophysiology of prolonged or delayed sleep initiation.
    RESULTS: The gene-wide analysis indicated differential methylation within or around 1818 unique genes across the sleep initiation measurements using self-report, actigraphy (ACT), and polysomnography (PSG), while GWAS-informed analysis yielded 67 genes. Gene hits were identified for bedtime (PSG), SOL (subjective, ACT and PSG) and SOT (subjective and PSG). DNA methylation within 12 genes was associated with both subjective and PSG-measured SOL, 31 with both ACT- and PSG-measured SOL, 19 with both subjective and ACT-measured SOL, and one gene (SMG1P2) had methylation sites associated with subjective, ACT- and PSG-measured SOL.
    CONCLUSIONS: Objective and subjective sleep initiation in adolescents is associated with altered DNA methylation in genes previously identified in adult GWAS of sleep and circadian phenotypes. Additionally, our data provide evidence for a potential epigenetic link between habitual (subjective and ACT) SOL and in-lab SOT and DNA methylation in and around genes involved in circadian regulation (i.e., RASD1, RAI1), cardiometabolic disorders (i.e., FADS1, WNK1, SLC5A6), and neuropsychiatric disorders (i.e., PRR7, SDK1, FAM172A). If validated, these sites may provide valuable targets for early detection and prevention of disorders involving prolonged or delayed SOT, such as insomnia, delayed sleep phase, and their comorbidity.
    Keywords:  Bedtime; DNA methylation; Epigenetics; Sleep initiation; Sleep latency
    DOI:  https://doi.org/10.1186/s13148-023-01553-2
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