Dataset Information

Functional Implications of the CLOCK 3111T/C Single-Nucleotide Polymorphism.

ABSTRACT: Circadian rhythm disruptions are prominently associated with bipolar disorder (BD). Circadian rhythms are regulated by the molecular clock, a family of proteins that function together in a transcriptional-translational feedback loop. The CLOCK protein is a key transcription factor of this feedback loop, and previous studies have found that manipulations of the Clock gene are sufficient to produce manic-like behavior in mice (1). The CLOCK 3111T/C single-nucleotide polymorphism (SNP; rs1801260) is a genetic variation of the human CLOCK gene that is significantly associated with increased frequency of manic episodes in BD patients (2). The 3111T/C SNP is located in the 3'-untranslated region of the CLOCK gene. In this study, we sought to examine the functional implications of the human CLOCK 3111T/C SNP by transfecting a mammalian cell line (mouse embryonic fibroblasts isolated from Clock(-/-) knockout mice) with pcDNA plasmids containing the human CLOCK gene with either the T or C SNP at position 3111. We then measured circadian gene expression over a 24-h time period. We found that the CLOCK3111C SNP resulted in higher mRNA levels than the CLOCK 3111T SNP. Furthermore, we found that Per2, a transcriptional target of CLOCK, was also more highly expressed with CLOCK 3111C expression, indicating that the 3'-UTR SNP affects the expression, function, and stability of CLOCK mRNA.

SUBMITTER: Ozburn AR

PROVIDER: S-EPMC4838618 | biostudies-literature | 2016

REPOSITORIES: biostudies-literature

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Functional Implications of the CLOCK 3111T/C Single-Nucleotide Polymorphism.

Ozburn Angela R AR Purohit Kush K Parekh Puja K PK Kaplan Gabrielle N GN Falcon Edgardo E Mukherjee Shibani S Cates Hannah M HM McClung Colleen A CA

Frontiers in psychiatry 20160421

Circadian rhythm disruptions are prominently associated with bipolar disorder (BD). Circadian rhythms are regulated by the molecular clock, a family of proteins that function together in a transcriptional-translational feedback loop. The CLOCK protein is a key transcription factor of this feedback loop, and previous studies have found that manipulations of the Clock gene are sufficient to produce manic-like behavior in mice (1). The CLOCK 3111T/C single-nucleotide polymorphism (SNP; rs1801260) i ...[more]

PMID: 27148095

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Project description:Background and Purpose- The E3 ubiquitin ligase MDM2 (murine double minute 2) is the main negative regulator of the p53 protein-a key player in neuronal apoptosis after ischemia. A functional single-nucleotide polymorphism in the human MDM2 gene promoter (rs2279744) regulates MDM2 protein expression. We investigated whether the MDM2 SNP309, by controlling p53-mediated apoptosis, determines functional outcome after stroke. Methods- Primary cortical neurons were subjected to oxygen and glucose deprivation. Mice were subjected to ischemic (transient middle cerebral artery occlusion) or hemorrhagic (collagenase injection) stroke models. Protein and mRNA levels of MDM2 and p53 were measured in both neuronal and brain extracts. The interaction of MDM2 with p53 was disrupted by neuronal treatment with nutlin-3a. siRNA was used to knockdown MDM2 expression. We analyzed the link between the MDM2 SNP309 and functional outcome, measured by the modified Rankin Scale scores, in 2 independent hospital-based stroke cohorts: ischemic stroke cohort (408 patients) and intracerebral hemorrhage cohort (128 patients). Results- Experimental stroke and oxygen and glucose deprivation induced the expression of MDM2 in the brain and neurons, respectively. Moreover, oxygen and glucose deprivation promoted MDM2 binding with p53 in neurons. Disruption of the MDM2-p53 interaction with nutlin-3a, or MDM2 knockdown by siRNA, triggered p53 accumulation, which increased neuronal susceptibility to oxygen and glucose deprivation-induced apoptosis. Finally, we showed that patients harboring the G allele in the MDM2 promoter had higher MDM2 protein levels and showed better functional outcome after stroke than those harboring the T/T genotype. The T/T genotype was also associated with large infarct volume in ischemic stroke and increased lesion volume in patients with intracerebral hemorrhage. Conclusions- Our results reveal a novel role for the MDM2-p53 interaction in neuronal apoptosis after ischemia and show that the MDM2 SNP309 determines the functional outcome of patients after stroke.

Project description:Single-nucleotide polymorphisms (SNPs) are widely used for whole-genome sequencing (WGS)-based subtyping of foodborne pathogens in outbreak and source tracking investigations. Mobile genetic elements (MGEs) are commonly present in bacterial genomes and may affect SNP subtyping results if their evolutionary history and dynamics differ from that of the bacterial chromosomes. Using Salmonella enterica as a model organism, we surveyed major categories of MGEs, including plasmids, phages, insertion sequences, integrons, and integrative and conjugative elements (ICEs), in 990 genomes representing 21 major serotypes of S. enterica We evaluated whether plasmids and chromosomal MGEs affect SNP subtyping with 9 outbreak clusters of different serotypes found in the United States in 2018. The median total length of chromosomal MGEs accounted for 2.5% of a typical S. enterica chromosome. Of the 990 analyzed S. enterica isolates, 68.9% contained at least one assembled plasmid sequence. The median total length of assembled plasmids in these isolates was 93,671 bp. Plasmids that carry high densities of SNPs were found to substantially affect both SNP phylogenies and SNP distances among closely related isolates if they were present in the reference genome for SNP subtyping. In comparison, chromosomal MGEs were found to have limited impact on SNP subtyping. We recommend the identification of plasmid sequences in the reference genome and the exclusion of plasmid-borne SNPs from SNP subtyping analysis.IMPORTANCE Despite increasingly routine use of WGS and SNP subtyping in outbreak and source tracking investigations, whether and how MGEs affect SNP subtyping has not been thoroughly investigated. Besides chromosomal MGEs, plasmids are frequently entangled in draft genome assemblies and yet to be assessed for their impact on SNP subtyping. This study provides evidence-based guidance on the treatment of MGEs in SNP analysis for Salmonella to infer phylogenetic relationship and SNP distance between isolates.

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Functional Implications of the CLOCK 3111T/C Single-Nucleotide Polymorphism.

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Functional Implications of the CLOCK 3111T/C Single-Nucleotide Polymorphism.

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