"It was previously believed that all cells during development contained the same chromatin remodelling proteins that unwind DNA, a process that is important for genes to be turned on. However, we identified one of these proteins, called Baf60c, that is expressed specifically in the developing heart," said Dr. Benoit Bruneau, the study's co-principal investigator, a Sick Kids scientist and an assistant professor of Molecular and Medical Genetics at the University of Toronto (U of T).
"When we completely suppressed the function of the Baf60c protein, there were dramatic cardiovascular defects. When we suppressed just half of the protein, the result was a defect that resembled one seen in infants," added Dr. Bruneau, also Canada Research Chair in Developmental Cardiology and member of U of T's Heart & Stroke/Richard Lewar Centre of Excellence.
Using a novel way of reducing gene function called in vitro RNAi, the team developed mouse models with different levels of the protein. They were then able to see the effects of the suppressed protein using optical projection tomography at the Mouse Imaging Centre at Sick Kids. Knockout mice, where a specific gene is replaced, or removed, allow researchers to have precise control over a specific gene in order to study its function.
"This new protein may provide new diagnostic tools and insights into how to treat cardiovascular problems," said Dr. Janet Rossant, the study's co-principal investigator and a senior investigator at the Samuel Lunenfeld Research Institute at MSH, as well as a professor of Molecular and Medical Genetics at U of T.
Congenital heart defects are among the most prevalent and serious conditions affecting children, occurring in approximately one out of 100 live births in Canada. The next steps for this research involve examining patients with congenital heart defects to see if they, like the mouse model, have this modified protein.
Other members of the research team include the study's co-lead authors Dr. Heiko Lickert of the Samuel Lunenfeld Research Institute at MSH and Dr. Jun Takeuchi of the Sick Kids Research Institute, Dr. Ingo von Both, Dr. Jeffrey Wrana, Dr. Fionnuala McAuliffe and Dr. S. Lee Adamson, all from the Samuel Lunenfeld Research Institute at MSH, and Dr. Mark Henkelman and Dr. Johnathon Walls from Sick Kids.
This research was supported by the Canadian Institutes of Health Research, the Heart and Stroke Foundation of Ontario, the March of Dimes Birth Defects Foundation, the National Cancer Institute of Canada, the Canada Foundation for Innovation, the Ontario Innovation Trust, the Ontario Research and Development Challenge Fund, and Sick Kids Foundation.
The Hospital for Sick Children, affiliated with the University of Toronto, is Canada's most research-intensive hospital and the largest centre dedicated to improving children's health in the country. Its mission is to provide the best in family-centred, compassionate care, to lead in scientific and clinical advancement, and to prepare the next generation of leaders in child health.
Mount Sinai Hospital is recognized nationally and internationally for its excellence in the provision of compassionate patient care, teaching and research. Our key priority programs are Infectious Diseases, Women's and Infants' Health, Cancer Surgery, General Internal and Subspecialty Medicine, Digestive Diseases, Arthritis and Orthopaedics, Emergency Medicine, Primary and Community Health and the Samuel Lunenfeld Research Institute. We are a University of Toronto affiliated patient care, teaching and research centre.
Journal
Nature