Functional implications of the CLOCK3111T/C single-nucleotide polymorphism

Angela R. Ozburn, Kush Purohit, Puja K. Parekh, Gabrielle N. Kaplan, Edgardo Falcon, Shibani Mukherjee, Hannah M. Cates, Colleen A. McClung

Research output: Contribution to journalArticle

16 Scopus citations

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.

Original languageEnglish (US)
Article number67
JournalFrontiers in Psychiatry
Volume7
Issue numberAPR
DOIs
StatePublished - Apr 21 2016

Keywords

  • Bipolar disorder
  • Cell culture
  • Circadian
  • Clock
  • Gene expression
  • Single-nucleotide polymorphism

ASJC Scopus subject areas

  • Psychiatry and Mental health

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