Clock: the story on HearLore

Clock

In 1997, a team of researchers led by Joseph Takahashi discovered a mouse that had simply stopped keeping time. This was not a mouse that was tired or sick, but one whose internal clock had run so far off schedule that it eventually ceased to function entirely. The gene responsible for this phenomenon was named CLOCK, a backronym for circadian locomotor output cycles kaput, chosen to reflect the chaotic behavior of the mutant animals. Takahashi and his colleagues had been screening mice treated with N-ethyl-N-nitrosourea, a chemical mutagen, looking for any disruption to their daily activity patterns. What they found was a heritable trait that defied the biological norm. Mice bred to be heterozygous for the mutation displayed a daily activity period of 24.4 hours, a noticeable stretch from the control group's 23.3 hours. However, the homozygous mutants, which carried two copies of the mutation, exhibited a period of 27.3 hours before eventually losing all circadian rhythmicity when placed in constant darkness. This discovery proved that intact CLOCK genes were necessary for normal mammalian circadian function, establishing the gene as a central player in the biological timing mechanism.

The Molecular Dance of Time

At the heart of the circadian rhythm lies a complex molecular dance involving the CLOCK protein and its partners. The CLOCK protein functions as a basic helix-loop-helix-PAS transcription factor, meaning it binds to specific DNA sequences to regulate gene expression. In fruit flies, newly synthesized CLOCK enters the nucleus and dimerizes with a partner protein called CYCLE, also known as dBMAL1 in mammals. This dimer recruits co-activators and becomes phosphorylated, allowing it to bind to E-box elements on the promoters of period and timeless genes. This binding stimulates the expression of these genes, leading to the production of PER and TIM proteins. As these proteins accumulate, they form a heterodimer that blocks the CLOCK-CYC complex from binding to the DNA, effectively shutting off its own production. The cycle is then reset when the doubletime kinase interacts with the complex, causing the degradation of both CLOCK and PER proteins, allowing the process to begin anew. This cycle of post-translational phosphorylation serves as the timing mechanism for the circadian clock, ensuring that the body's internal processes remain synchronized with the external environment.

Metabolism and the Clockwork Body

The influence of the CLOCK gene extends far beyond the simple regulation of sleep and wake cycles, weaving itself into the very fabric of metabolism. The CLOCK-BMAL dimer activates the transcription of the Nicotinamide phosphoribosyltransferase gene, which codes for the NAMPT protein. This protein is part of a series of enzymatic reactions that convert niacin to NAD, a molecule essential for cellular energy. SIRT1, an enzyme that requires NAD for its activity, then uses these increased NAD levels to suppress BMAL1 through deacetylation. This suppression results in less transcription of the NAMPT gene, less NAMPT protein, and consequently less NAD made, which in turn reduces the suppression of the CLOCK-BMAL dimer. This creates a self-sustaining oscillatory loop that links the circadian clock directly to metabolic processes. The close relationship between metabolism and circadian clocks is highlighted by the fact that disruptions in this loop can lead to metabolic syndrome symptoms, altered plasma glucose levels, and disrupted food intake rhythms in mutant mice.

Common questions

What is the CLOCK gene and how was it discovered?

The CLOCK gene was discovered in 1997 by a team of researchers led by Joseph Takahashi. This team identified a mouse mutant whose internal clock had run so far off schedule that it eventually ceased to function entirely. The gene was named CLOCK as a backronym for circadian locomotor output cycles kaput to reflect the chaotic behavior of the mutant animals.

How does the CLOCK protein regulate circadian rhythms in mammals?

The CLOCK protein functions as a basic helix-loop-helix-PAS transcription factor that binds to specific DNA sequences to regulate gene expression. In mammals, the CLOCK protein dimerizes with a partner protein called CYCLE or dBMAL1 to bind to E-box elements on the promoters of period and timeless genes. This binding stimulates the expression of these genes, leading to the production of PER and TIM proteins which eventually block the CLOCK-CYC complex from binding to the DNA.

What is the relationship between the CLOCK gene and human metabolism?

The CLOCK-BMAL dimer activates the transcription of the Nicotinamide phosphoribosyltransferase gene which codes for the NAMPT protein. This protein is part of a series of enzymatic reactions that convert niacin to NAD, a molecule essential for cellular energy. Disruptions in this loop can lead to metabolic syndrome symptoms, altered plasma glucose levels, and disrupted food intake rhythms in mutant mice.

When did the CLOCK gene originate in evolutionary history?

The origins of the CLOCK gene stretch back hundreds of millions of years with its roots embedded in the earliest forms of life. The common ancestor of CLOCK and BMAL1 likely predates the insect-vertebrate split roughly 500 million years ago. Cryptochromes are likely descendants of kaiC resulting from a genome duplication predating the Cambrian explosion.

How does the CLOCK gene affect human brain development and sleep disorders?

In humans, the CLOCK gene plays a critical role in the development and function of the brain particularly in the regulation of neuronal migration and cortical expansion. Polymorphisms in the 3111C allele of the 3' flanking region of the CLOCK gene have been linked to morning or evening preference in adults. These polymorphisms can affect mRNA stability and lead to conditions such as insomnia or other sleep disorders.

What health conditions are linked to mutations in the CLOCK gene?

Mutations in the CLOCK gene can lead to a wide array of physiological and behavioral disorders ranging from sleep disturbances to mood disorders. In humans, a polymorphism in Clock rs6832769 may be related to the personality trait agreeableness while another single nucleotide polymorphism 3111C is associated with diurnal preference and increased insomnia. These mutations are also linked to difficulty losing weight and the recurrence of major depressive episodes in patients with bipolar disorder.