Novel mechanism regulating circadian rhythm identified

November 02, 2015

"Based on the fact that BMAL1 and NPAS2 work together within the circadian clock, it seems highly unlikely that these two nuclear receptors would only regulate one of them," Burris said. "Our study shows for the first time that, like BMAL1, NPAS2 is also a direct target for ROR? and REV-ERB?. This discovery makes this complex a very good therapeutic target."

The expression of ROR? and REV-ERB? follows a 24-hour circadian pattern (with opposing phases) leading to the correct circadian pattern of gene expression of BMAL1 and NPAS2.

"We think it's something of a competition between these two receptors for binding to promoters of these genes that triggers either the activation (ROR?) or repression (REV-ERB?) of the gene," Burris said.

Nuclear receptors make tempting drug targets because they can bind directly to DNA and activate genes through specific ligands??molecules that affect receptor behavior??such as the sex hormones, vitamins A and D, and glucocorticoids, which modulate the body's response to stress. Nuclear receptors have been implicated in a number of cancers, including prostate, breast, and colon cancers, and other diseases as well, including type 2 diabetes, atherosclerosis, and metabolic syndrome.

The other important aspect of nuclear receptors is their practicality. Scientists can design small molecule therapeutics to force them to change their ways. Burris said that he has already identified several new synthetic ligands (drug like molecules) for both receptors.

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