Researchers at the Centre for Genomic Regulation (CRG), the Bellvitge Biomedical Research Institute (IDIBELL), and the University of Barcelona have uncovered the role of a gene that is critical to boosting the number of insulin-producing cells during the early formation of the pancreas.
The findings are published in the journal Genes and Development in a paper titled, “REST is a major negative regulator of endocrine differentiation during pancreas organogenesis.”
Using mouse and zebrafish models, along with human pancreatic organoids, the researchers studied the RE1 Silencing Transcription Factor gene, also known as REST.
“Multiple transcription factors have been shown to promote pancreatic β-cell differentiation, yet much less is known about negative regulators,” wrote the researchers. “Earlier epigenomic studies suggested that the transcriptional repressor REST could be a suppressor of endocrinogenesis in the embryonic pancreas. However, pancreatic REST knockout mice failed to show abnormal numbers of endocrine cells, suggesting that REST is not a major regulator of endocrine differentiation. Using a different conditional allele that enables profound REST inactivation, we observed a marked increase in pancreatic endocrine cell formation.”
The researchers observed that REST is expressed in embryonic pancreatic cells. They did not detect REST activity in adult beta-cells that produce insulin. Using mouse models, they discovered that knocking the REST gene out at the early embryonic stage, before the pancreas is formed, resulted in doubling the number of insulin-producing cells. The cells were also maintained into adulthood.
Inactivating REST was not able to boost beta cell formation after the pancreas has already formed. Mice with inactivated rest soon after birth exhibited a short-lived boost to endocrine cell formation, but this was not sustained through adulthood. Inactivating REST in human pancreatic organoids did not lead to beta-cell formation, though researchers did detect increased activity of endocrine genes.
“Though important for the development of the pancreas, we have shown that REST is not the sole guardian of endocrine differentiation. However, if one day we come up with a future cocktail of drugs to boost insulin-producing cells in the pancreas, I suspect that REST inhibitors would be part of the recipe. We are now testing whether REST inhibitors can be used to artificially boost the formation of beta cells in a dish,” said Jorge Ferrer, senior author of the study and group leader of regulatory genomics and diabetes at the CRG.
“REST joins a very short list of dominant suppressors of endocrine differentiation during pancreas development,” added Meritxell Rovira, co-author of the study and researcher with joint affiliation with IDIBELL and the University of Barcelona. “REST modulators will most likely play an important role for future manipulations to promote endocrinogenesis in experimental model systems or replacement therapies for diabetes.”
