Researchers at the University of Virginia School of Medicine have turned traditional beliefs about how vital hormone receptors work in cells, a finding that could fuel the development of drugs for diabetes and related metabolic disorders, cancer, and other diseases.
Senior Researcher Irina M. Bochkis is Assistant Professor of Pharmacology at the UVA School of Medicine. (Photo by Dan Addison, University of Virginia)
The scientists in the Department of Pharmacology at UVA are outlining a completely new paradigm to explain the activation of a type of hormone receptor called type II receptors, which are located in the nucleus of our cells. These receptors, along with other critical processes, play an important role in how our bodies use cholesterol and glucose.
“Nuclear receptors are the only class of DNA-binding proteins that are drug-capable. Drug development focused solely on creating artificial hormones to replace the natural ones and activate the receptor because everyone believed that the binding of the receptor to DNA was constant, ”said lead researcher Irina M. Bochkis, PhD. “To everyone’s surprise, we find that the DNA has to be opened for the receptor to bind. Different parts of the DNA become accessible to different artificial hormones, some of which lead to positive and some to harmful effects. If we can target the places in the DNA that lead to beneficial effects and avoid access to places that would lead to adverse effects, the effectiveness of the drugs would be greatly improved. “
Understand hormone effects
Scientists have hypothesized that two important hormone receptors known as FXR & LXRα are permanently attached to the DNA in the nucleus of our cells. However, Bochkis and her team found that this was not the case. Instead, a complex cascade of events is required to activate the hormone receptors, they noted.
A key player in this process is a protein called Foxa2. Our DNA is trapped in our chromosomes in a form known as chromatin; Foxa2 turns the key in this lock. This will temporarily open the chromatin. As soon as this happens, hormone binding can occur, the UVA scientists found.
Foxa2 also plays other important roles, they found. After opening the chromatin, it activates the correct receptor and suppresses a competing receptor. Computer analysis by researcher Nihal Reddy, an undergraduate student, was crucial to prove this point.
Based on their results, the researchers have called Foxa2 a “gatekeeper” in the hormone binding process. And it could also act as a gatekeeper for other type II receptors in the nucleus, the researchers conclude.
“People didn’t believe us because they had relied on another model for so long. Our first results only described LXRα. We decided to include FXR to show that Foxa2 opens DNA to multiple receptors in a common mechanism, ”said researcher Xiaolong Wei, co-first author of a new scientific paper outlining the results. “To do this, we had to double the number of the numerous genomic experiments that we performed, which took a while. But it’s worth it.”
Another surprising finding: Until now, scientists thought that the binding of ligands (or artificial hormones) only led to the activation of genes by the receptor. But the new work by Bochkis and their employees turns this belief on its head. Ligand binding forces Foxa2 and the nuclear receptor to interact; this leads to the opening of the DNA by Foxa2 and subsequent receptor binding and gene activation. Foxa2 and the nuclear receptor don’t interact without the ligand, they found.
Now, by teaching endocrinology, I can finally show the correct model of receptor activation instead of saying the textbook hasn’t kept up with the research. Our results will change the way people approach drug design and hopefully lead to formulations that have no harmful side effects. “
Irina M. Bochkis, PhD, Senior Researcher
The researchers have published their results in the journal Molecular Metabolism. The research team consisted of Jessica Kain, Xiaolong Wei, Nihal A. Reddy, Andrew J. Price, Claire Woods and Irina Bochkis.
The research was supported by the National Diabetes and Digestive and Kidney Diseases Institute of the National Institutes of Health, R01 Award DK121059.
University of Virginia Medical School
Kain, J., et al. (2021) The pioneer factor Foxa2 enables the ligand-dependent activation of the type II nuclear receptors FXR and LXRα. Molecular metabolism. doi.org/10.1016/j.molmet.2021.101291.