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.

Genetic polymorphisms associated with circadian rhythm dysregulation provide new perspectives on bipolar disorder

“…The SCN regulates the biological rhythms of the organism with oscillations in a 24‐hour cycle caused by self‐sustaining loops and self‐regulated transcription/translation of the so‐called circadian genes. The molecular machinery of the CR comprises > 20 circadian genes, the main components being the Clock circadian regulator ( CLOCK gene), Aryl hydrocarbon receptor nuclear translocator like ( ARNTL gene), Period circadian regulator ( PER 1, 2 and 3 gene), Cryptochrome circadian regulator ( CRY 1 and 2 gene) . Briefly, the CLOCK‐ARNTL protein complex stimulates expression of PER ( 1 , 2 and 3 ) and CRY ( 1 and 2 ), which are negative regulators of the CR.…”

“…The symptoms of BD are serious and include unusual changes in mood, energy metabolism, activity levels and the ability to perform activities of daily living . BD places substantial burdens on society due to a greater loss of productivity in BD patients when compared to patients with other mood disorders . Because it is a serious, chronic, disabling and common mental disorder, affecting 1%‐3% of the US population (for a review, see Geoffroy et al), understanding of its pathophysiological mechanisms, diagnostic forms and therapeutic interventions has increasingly been sought, although, the heterogeneous, episodic and recurrent nature of BD poses challenges for diagnosis and treatment efficacy.…”

“…One of the hallmark features of BD is dysfunction of the circadian rhythm (CR), a system found in most living things that induces biochemical, molecular and functional changes in organisms within a period of about 24 hours. It regulates a range of processes, from our sleep to metabolism and neural activity . Changes in CR, especially in the sleep‐wake cycle, are common in BD, as well as in most other neuropsychiatric disorders .…”

An overview of mice models: a key for understanding subtypes of mania

“…The Clock knockout has allowed the identification of the functional consequences of some polymorphisms in the genes that regulate the molecular pathways of circadian rhythms. In the case of Per1 (one of the CLOCK genes), the variant 3111T/C alters transcriptional efficiency and therefore the physiological processes that control sleep-wake dynamics, body temperature, and the hormonal changes related to the molecular clock (Ozburn, et al 2016). …”

CLOCK 3111T/C genetic variant influences the daily rhythm of autonomic nervous function: relevance to body weight control

“…The molecular basis for the circadian clocks consists of a family of proteins that function together in a transcriptional–translational feedback loop with the CLOCK protein as a key transcription factor of this loop 12 . A recent study showed that the CLOCK 3111C SNP resulted in higher expression of CLOCK and also increased the expression of PER2 — a transcriptional target of CLOCK 13 , suggesting a functional role of the genetic variant in the circadian control and, thus, altered circadian/daily rhythms of behavior and physiology in human C carriers.…”