Dataset Information

PTBP1 Positively Regulates the Translation of Circadian Clock Gene, Period1.

ABSTRACT: Circadian oscillations of mRNAs and proteins are the main features of circadian clock genes. Among them, Period1 (Per1) is a key component in negative-feedback regulation, which shows a robust diurnal oscillation and the importance of circadian rhythm and translational regulation of circadian clock genes has been recognized. In the present study, we investigated the 5'-untranslated region (5'-UTR) of the mouse core clock gene, Per1, at the posttranscriptional level, particularly its translational regulation. The 5'-UTR of Per1 was found to promote its translation via an internal ribosomal entry site (IRES). We found that polypyrimidine tract-binding protein 1 (PTBP1) binds to the 5'-UTR of Per1 and positively regulates the IRES-mediated translation of Per1 without affecting the levels of Per1 mRNA. The reduction of PTBP1 level also decreased the endogenous levels of the PER1 protein but not of its mRNA. As for the oscillation of PER1 expression, the disruption of PTBP1 levels lowered the PER1 expression but not the phase of the oscillation. PTBP1 also changed the amplitudes of the mRNAs of other circadian clock genes, such as Cryptochrome 1 (Cry1) and Per3. Our results suggest that the PTBP1 is important for rhythmic translation of Per1 and it fine-tunes the overall circadian system.

SUBMITTER: Kim W

PROVIDER: S-EPMC7555454 | biostudies-literature | 2020 Sep

REPOSITORIES: biostudies-literature

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PTBP1 Positively Regulates the Translation of Circadian Clock Gene, Period1.

Kim Wanil W Shin Jae-Cheon JC Lee Kyung-Ha KH Kim Kyong-Tai KT

International journal of molecular sciences 20200921 18

Circadian oscillations of mRNAs and proteins are the main features of circadian clock genes. Among them, Period1 (Per1) is a key component in negative-feedback regulation, which shows a robust diurnal oscillation and the importance of circadian rhythm and translational regulation of circadian clock genes has been recognized. In the present study, we investigated the 5'-untranslated region (5'-UTR) of the mouse core clock gene, Per1, at the posttranscriptional level, particul ...[more]

PMID: 32967200

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Project description:Circadian dysfunction is a common attribute of many neurodegenerative diseases, most of which are associated with neuroinflammation. Circadian rhythm dysfunction has been associated with inflammation in the periphery, but the role of the core clock in neuroinflammation remains poorly understood. Here we demonstrate that Rev-erbα, a nuclear receptor and circadian clock component, is a mediator of microglial activation and neuroinflammation. We observed time-of-day oscillation in microglial immunoreactivity in the hippocampus, which was disrupted in Rev-erbα-/- mice. Rev-erbα deletion caused spontaneous microglial activation in the hippocampus and increased expression of proinflammatory transcripts, as well as secondary astrogliosis. Transcriptomic analysis of hippocampus from Rev-erbα-/- mice revealed a predominant inflammatory phenotype and suggested dysregulated NF-κB signaling. Primary Rev-erbα-/- microglia exhibited proinflammatory phenotypes and increased basal NF-κB activation. Chromatin immunoprecipitation revealed that Rev-erbα physically interacts with the promoter regions of several NF-κB-related genes in primary microglia. Loss of Rev-erbα in primary astrocytes had no effect on basal activation but did potentiate the inflammatory response to lipopolysaccharide (LPS). In vivo, Rev-erbα-/- mice exhibited enhanced hippocampal neuroinflammatory responses to peripheral LPS injection, while pharmacologic activation of Rev-erbs with the small molecule agonist SR9009 suppressed LPS-induced hippocampal neuroinflammation. Rev-erbα deletion influenced neuronal health, as conditioned media from Rev-erbα-deficient primary glial cultures exacerbated oxidative damage in cultured neurons. Rev-erbα-/- mice also exhibited significantly altered cortical resting-state functional connectivity, similar to that observed in neurodegenerative models. Our results reveal Rev-erbα as a pharmacologically accessible link between the circadian clock and neuroinflammation.

Dataset Information

PTBP1 Positively Regulates the Translation of Circadian Clock Gene, Period1.

Publications

PTBP1 Positively Regulates the Translation of Circadian Clock Gene, <i>Period1</i>.

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