The mechanisms underlying the circadian control of gene expression in peripheral tissues and influencing many biological pathways are poorly defined. Factor VII (FVII), the protease triggering blood coagulation, represents a valuable model to address this issue in liver since its plasma levels oscillate in a circadian manner and its promoter contains E-boxes, which are putative DNA-binding sites for CLOCK-BMAL1 and NPAS2-BMAL1 heterodimers and hallmarks of circadian regulation. The peaks of FVII mRNA levels in livers of wild-type mice preceded those in plasma, indicating a transcriptional regulation, and were abolished in Clock(-/-); Npas2(-/-) mice, thus demonstrating a role for CLOCK and NPAS2 circadian transcription factors. The investigation of Npas2(-/-) and Clock(Delta19/Delta19) mice, which express functionally defective heterodimers, revealed robust rhythms of FVII expression in both animal models, suggesting a redundant role for NPAS2 and CLOCK. The molecular bases of these observations were established through reporter gene assays. FVII transactivation activities of the NPAS2-BMAL1 and CLOCK-BMAL1 heterodimers were (i) comparable (a fourfold increase), (ii) dampened by the negative circadian regulators PER2 and CRY1, and (iii) abolished upon E-box mutagenesis. Our data provide the first evidence in peripheral oscillators for an overlapping role of CLOCK and NPAS2 in the regulation of circadianly controlled genes.
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http://dx.doi.org/10.1128/MCB.01931-07 | DOI Listing |
Peptides
January 2025
Department of Clinical Biochemistry, Copenhagen University Hospital - Bispebjerg and Frederiksberg, Copenhagen, Denmark; Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
Expression of prokineticin 2 (PK2) mRNA in the suprachiasmatic nucleus (SCN), also knowns as the brain's clock, exhibits circadian oscillations with peak levels midday, zeitgeber time (ZT) 4, and almost undetectable levels during night. This circadian expression profile has substantially contributed to the suggested role of PK2 as an SCN output molecule involved in transmitting circadian rhythm of behavior and physiology. Due to unreliable specificity of PK2 antibodies, the 81 amino acid protein has primarily been studied at the mRNA level and correlation between circadian oscillating mRNAs and protein products are infrequent.
View Article and Find Full Text PDFBiomed Pharmacother
January 2025
Department of Experimental Medicine, Sapienza University of Rome, Rome 00161, Italy. Electronic address:
The abundance and behaviour of all hematopoietic components display daily oscillations, supporting the involvement of circadian clock mechanisms. The daily variations of immune cell functions, such as trafficking between blood and tissues, differentiation, proliferation, and effector capabilities are regulated by complex intrinsic (cell-based) and extrinsic (neuro-hormonal, organism-based) mechanisms. While the role of the transcriptional/translational molecular machinery, driven by a set of well-conserved genes (Clock genes), in nucleated immune cells is increasingly recognized and understood, the presence of non-transcriptional mechanisms remains almost entirely unexplored.
View Article and Find Full Text PDFAlzheimers Dement
December 2024
Yale University, New Haven, CT, USA.
Background: Alcohol Use Disorder (AUD) affects over 15 million individuals in the United States, contributing to oxidative stress, neuroinflammation, and elevating the risk of neurodegeneration. Despite this, the connection between AUD and aging conditions, particularly Alzheimer's disease (AD), remains unclear. AD, with a heritability of 60-80%, is genetically linked, necessitating an exploration of the molecular implications of AUD and genetic susceptibility to AD.
View Article and Find Full Text PDFAlzheimers Dement
December 2024
New York State Institute for Basic Research in Developmental Disabilities, Staten Island, NY, USA.
Background: Circadian rhythm disorder is not only a characteristic of neurodegenerative diseases but may participate in driving the pathological development in early stages of these diseases. Transactive response DNA-binding protein of 43 kDa (TDP-43) knockdown and its pathological aggregation are associated with severe neurodegenerative diseases such as amyotrophic lateral sclerosis.
Methods: C57BL/6 mice were sleep deprived and sarcrificed at ZT0, ZT6, ZT12, and ZT18 and detected by Western blots.
Background: Biomarkers that predict the heterogenous nature and late onset of cognitive decline are needed to evaluate geroscience interventions designed to delay or prevent the progression of Alzheimer's Disease and related dementias (ADRD). The DunedinPACE epigenetic clock is designed to measure pace of biological aging, and is therefore a promising candidate biomarker. Here we (1) investigate if DunedinPACE is associated with cognitive aging, and (2) the extent to which these associations are independent of education.
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