Toronto researchers discover how genes remember their function

Breakthrough may help understand schizophrenia and cancer

(Toronto, ON, September 3, 2009) - Researchers at the Samuel Lunenfeld Research Institute of Mount Sinai Hospital, The Hospital for Sick Children (SickKids), and The University of Toronto have made a breakthrough in understanding how genes remember their past experience through Polycomb Response Elements (PRE), which are memory modules that switch genes on or off. This discovery may lead to insights into diseases such as schizophrenia and cancer.

In a study published in the September 4 issue of the journal Cell, Toronto scientists have identified the first mammalian PRE - previously it was only confirmed that PREs existed in fruit flies. Dr. Sabine Cordes, a Senior Investigator at the Lunenfeld, made the discovery together with her graduate student Angela Sing, by studying the Kreisler gene (MafB) – which is turned on in the hindbrain - in mouse models.

“We found that, as in flies, the PRE we discovered is located in a very precise region of the DNA, but is at quite a distance from the gene it is switching on or off,” explains Sing. “This came as a surprise, because in mammals, scientists only had been looking at the regions near the genes themselves. That is like looking for a light switch beside a light fixture when the switch is often far away.”

Dr. Cordes further explains that “now that we know what a vertebrate PRE looks like, we may be able to find more PREs and investigate what roles they play in mental illness or cancer. In our study, we concluded that this particular PRE sets the Kreisler gene’s genetic memory (turning it on or off). This gene has an impact in nervous system development and, possibly, cancers such as leukemia.”

The researchers also found that that the M33/Cbx2, a polycomb-type protein that may be associated with schizophrenia, controls the Kreisler PRE. They found that reducing levels of M33 caused some of the Kreisler-expressing cells to forget what they were trying to become (their function).

“This study is the first to identify a PRE memory module in mammals and provides the first glimpse into how they function” says Dr. James Ellis, a Senior Scientist at SickKids and Associate Professor of Molecular Genetics at The University of Toronto, who worked on the study with Dr. Howard Lipshitz, a Senior Scientist at SickKids and Professor and Chair of Molecular Genetics at The University of Toronto. “A particularly striking aspect of the research is that the Kreisler PRE worked when we put it into flies. So, these genetic memory modules were already present hundreds of millions of years ago in our last common ancestor. It’s this remarkable evolutionary conservation of fundamental processes that makes studying simple organisms like flies lead to major insights into human development and disease.”

This study received funding from the Canadian Institutes for Health Research.

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Toronto researchers discover how genes remember their function

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