Micro Control for Insulin


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(l-r) Standing: Sharon Kredo, Dr. Tali Melkman Zehavi, Roni Oren. Sitting: Dr. Eran Hornstein, Natali Rivkin, Amitai Mandelbaum

The water came and extinguished the fire that burned the stick that beat the dog that bit the cat that ate the goat that father bought for two zuzim. – Had Gadya (from the Passover Haggada)

According to Dr. Eran Hornstein of the Molecular Genetics Department, a Had-Gadya-like scenario takes place daily in the pancreas, and it goes something like this: The microRNA slew the negative transcription factor that inhibited the gene that codes for insulin that regulates sugar in the body.
The focus of Hornstein’s research is on one of those players: microRNAs – short bits of genetic material that don’t code for proteins. Nonetheless, these tiny sequences of code perform all sorts of regulatory functions in the cells, and they may be involved in a number of complex diseases. In a series of experiments over the past four years, Hornstein and his research team have been examining the role of microRNAs in the pancreatic beta cells – the producers of insulin. Their findings not only shed new light on the way that insulin production is controlled – they may aid, in the future, in the diagnosis and treatment of diabetes.

The team included Dr. Tali Melkman Zehavi, students Roni Oren, Sharon Kredo, Amitai Mandelbaum and Tirosh Shapira, and lab technician Natali Rivkin. To begin, the researchers first checked to see whether microRNAs were involved in any way in pancreatic function. Using advanced genetic techniques to prevent microRNA from forming in the pancreases of mice, they came up with a clear answer: Without microRNA, the mice did not produce insulin, and they soon developed the symptoms of diabetes.

Next, as the team probed further, they identified the step in the gene-to-protein process that is dependent on microRNA control. That step is transcription – the stage in which the information encoded in the genes is copied out for use in protein production. But this finding left them with further questions. “It’s not obvious that microRNAs would be involved in the control of insulin transcription, as they are more often known to regulate post-transcriptional events in the cell,” says Hornstein. “We had to sit down and come up with a hypothesis that would include another intermediate – a so-called negative transcription factor.”

All cells carry the genetic information needed to produce insulin, but only beta cells actually do so. One of the reasons for this is that other cells actively repress insulin production; negative transcription factors keep the genetic information from ever getting transcribed. Beta cells, in contrast, normally maintain a profusion of the transcription factors that bind to genes and initiate insulin production, and very few of the negative factors that inhibit this process. Further testing showed that microRNA affects only the negative transcription factors in beta cells, squelching them so that insulin production can proceed.

Finally, Hornstein and his team identified four specific microRNA genes that appear to promote insulin synthesis.

This research recently appeared in the EMBO Journal. By showing how microRNA affects insulin production, Hornstein and his team have added a new layer to our understanding of the mechanisms involved in diabetes. Their findings may pave the way, in the future, to better tools for diagnosing the disease and eventually to better treatment.

Dr. Eran Hornstein's research is supported by the Nella and Leon Benoziyo Center for Neurological Diseases; the Women's Health Research Center funded by the Bennett-Pritzker Endowment Fund, the Marvelle Koffler Program for Breast Cancer Research, the Harry and Jeanette Weinberg Women's Health Research Endowment, and the Oprah Winfrey Biomedical Research Fund;the Nathan, Shirley, Philip and Charlene Vener New Scientist Fund; the Legacy Heritage Fund; and the Wolfson Family Charitable Trust. Dr. Hornstein is the incumbent of the Helen and Milton A. Kimmelman Career Development Chair.