A familiar gene in an unfamiliar role
The scientists zeroed in on HNF4A, a well-known protein believed to be involved in the embryonic development of liver, kidney and intestine. The team examined liver and colon cells derived from mice and humans, and unexpectedly discovered that HNF4A is intimately tied to the circadian clock in these organs. They found that the protein represses the operation of CLOCK and BMAL1, which act as key molecular cogs that drive the circadian rhythms in mammals.
In the cell nucleus, nuclear receptors receive chemical signals from the cell and partner with other proteins to unleash specific genes that regulate cell development, homeostasis and metabolism. The receptors act at the crossroads of cellular circuitry by integrating information necessary for normal cell function. Nuclear receptors are potential targets for drugs to fight diseases, including reproductive disorders, inflammation, cancer, diabetes, cardiovascular disease and obesity. The researchers found for the first time that the circadian clock modulates daily cycles of HNF4A’s classical functions as a nuclear receptor.
“Inside the cell, the cogs of the clock are universal, but the hands of the clock are specific to each organ, so how the clock does its work in each cell is different,” Kay explained. “So, in the liver, we looked at tissue-specific proteins and found that HNF4A is tied to the circadian clock, is regulated by the clock and cycles with the clock and, in turn, regulates the clock. That’s the new finding here and it’s a big jump forward.”