The circadian clock is a biological timekeeper. As it ticks through its 24-hour cycle, some 10 to 15 percent of our genes dance to its beat, stirring us to wake and eat and lulling us to sleep. Remarkably, this complex dance is choreographed by only a handful of master regulatory genes, two of which recently were found to not only regulate clock activity but also influence the metabolism of nutrients.
, reported in the journal Nature
, revealed that the genes Rev-erb-α
, which previously were thought to be of only minor importance in circadian regulation, actually are key components of the feedback loop that drives the circadian clock. They work in concert with Bmal1
, a gene known to play a central role in the activation of circadian-sensitive genes. The new study indicated that as many as 68 percent of these associated genes are also influenced by the Rev-erb
The researchers uncovered the new information using a series of mouse models, one of which was described as an inducible double knockout, since treatment of the mice with the drug tamoxifen resulted in deactivation of both Rev-erb genes. In wheel-running tests in darkness (a method of assessing circadian behavior in mice), tamoxifen-treated mice ran on their wheels for much shorter periods of time compared with normal mice. They also suffered from metabolic abnormalities, such as increased levels of sugar and triglycerides in their blood.
Under dark conditions the mice experienced a drop in their respiratory exchange ratio (the ratio of CO2 exhaled to O2 inhaled in a breath), which was suggestive of significant metabolic dysregulation. This conclusion was supported by further genomic investigation, which revealed that the Rev-erb genes work in tandem to regulate hundreds of genes that influence metabolism, including those that govern cholesterol levels and the metabolism of bile acids.
The study is not the first to reveal a link between circadian clock regulation and metabolism. In 2008, for instance, scientists reported that a protein known as CLOCK regulates circadian activity as well as cellular energy consumption, performing the latter task in cooperation with SIRT1, a protein that earlier work had indicated was involved in intracellular regulation. The CLOCK protein has also been shown to work in conjunction with BMAL1 to activate circadian-driven genes in response to alternating light and dark cycles (in some animals circadian rhythm can be maintained in the absence of these cues, although the rhythm eventually falls out of sync with natural light-dark cycles).
The latest study proposes a model in which a CLOCK-BMAL1 protein complex activates circadian rhythm-associated gene expression, including the expression of the Rev-erb genes. The proteins encoded by Rev-erb-α and Rev-erb-β then act through a negative feedback mechanism to suppress clock activity. This activating-deactivating rhythm in turn sustains the 24-hour clock cycle.
While the proposed model highlights the complexity of the molecular mechanisms underlying circadian rhythm, the results could have meaningful impacts on human health, particularly regarding the treatment of jet lag, sleep disorders, and metabolic diseases such as diabetes. Such conditions potentially could be treated with drugs that target defective master circadian regulatory genes or proteins, thereby restoring biological rhythm and metabolic homeostasis.