Pioneer in histone research searches for epigenetic biomarkers
As a teenager, Dr. Jim Davie spent hours experimenting in a backyard shed in Winnipeg, Manitoba, where his parents had banished his chemistry kit.
“I’ve always liked dealing with test tubes, chemical reactions and biology, especially in the context of the cell,” he admits. “When I started university, biochemistry was a logical choice, because it combined my love of chemistry and biology.”
Davie, a professor in the Department of Biochemistry and Medical Genetics, senior scientist at the Research Institute in Oncology and Hematology, University of Manitoba, and scientist at the Children’s Hospital Research Institute of Manitoba, holds a Tier 1 Canada Research Chair in Chromatin Dynamics. He was inducted as a fellow into the Canadian Academy of Health Sciences and the Royal Society of Canada in 2015.
He studies the science of epigenetics: how environmental and genetic factors join forces to influence life in normal and cancerous cells.
What are epigenetics?
DNA contains many different genes, Davie explains. Like a CD, it’s filled with many different songs. The study of genetics is like listening to all songs on the CD. A wrong note – a genetic mutation – sounds awful, and you know that something’s wrong with the music.
“Epigenetics is deciding what songs you’re going to play.” Epigenetic factors influence the choice of songs on your CD: country and western, rap, new age or classical. The specific songs in your musical repertory are unique – just like you.
What are histones?
Davie is known for groundbreaking findings in histone research. In the nucleus of every human cell, groups of histone molecules form special structures called nucleosomes. These structures curl the DNA around them, forming a DNA-protein complex, the basic building block of chromatin and chromosomes.
“Histones are small, basic proteins,” Davie explains. “You can easily isolate them from cells. They have about the same mass as DNA.”
During his career, Davie and other epigenetic researchers have expanded our knowledge of chromatin structure and function. For example, they discovered that four pairs of individual histones – H2A, H2B, H3 and H4 – form the nucleosome.
“In the beginning, we thought that the nucleosome was really just a structural entity. We thought it was just helping to compact DNA in a very orderly fashion. Later on, we started to understand histone modifications and how they sent information into the nuclear environment.”
Davie and others in the field found that natural modifications of histones, for example, how tightly or loosely DNA winds around histone spools, affect how cells manufacture proteins, communicate with other cellular components to kick start cellular processes, and more.
According to Davie, depending on where it’s located, a histone modification can orchestrate whether a gene is turned off or on, “so it can actually regulate gene expression. We now think of nucleosomes not only as structural units but as signalling molecules.” In other words, they can kick off events at specific locations in chromatin.
Davie has made some rewarding findings. “Going back to my early work on histones, one thing was clear. Histone deacetylase levels are deregulated in cancer.”
Histone deacetylases are enzymes that modify histone molecules in a way that allows them to wrap DNA more tightly around nucleosomes. If wrapped too tightly, the manufacturing machinery within cells cannot access genes to make proteins. Such modifications may kick start the mis-expression of genes and the production of abnormal proteins, leading to cancer.
Early in his career, Davie discovered that sodium butyrate was an inhibitor of histone deacetylase and that histone deacetylase inhibitors could stop cancer cell growth. His original findings were published in Cell.
“Those early studies indicated the road for further study,” he says. They paved the way for development of a new class of anticancer drugs for treatment of certain kinds of cancer.
“Our studies were pivotal for moving forward,” he says. “We provided the knowledge. Other groups took it into translation and, now, it’s in the clinic.”
Davie earned a BSc and PhD in biochemistry from the University of British Columbia, where he chose to study histone modification under Dr. Peter Candido, who had worked with Dr. Gordon Dixon and other godfathers of epigenetics, then a burgeoning new field of medical research.
“I really liked what he was doing, and I never regretted making that decision, not even at the get-go.”
Davie pursued post-doctoral studies in chromatin structure and function at the University of Oregon. Then, in 1983, he was offered a faculty position at the University of Manitoba’s Faculty of Medicine. Lured by a $30,000 grant to start a research laboratory, Davie moved back to Winnipeg. He equipped the lab with grant funds from the Manitoba Health Research Council (MHRC), founded only a year earlier.
In addition to basic research on chromatin, Davie’s team is working on developing epigenetic biomarkers, e.g., biochemical tests that signal a woman’s risk of breast cancer and identify children who have fetal alcohol spectrum disorders (FASDs).
Fetal alcohol spectrum disorders
“We’re looking for a tool that will become part of the diagnostic repertoire for clinicians who want to know whether a child has FASD.”
Only about 10% of children with FASD have visible signs of the disorder. To confirm a diagnosis, the remaining majority must undergo a battery of high-cost tests. Because of these roadblocks, many children remain undiagnosed. Without proper treatment, children may do poorly in school, lack the skills to cope with mental health issues, and end up in trouble with the law.
Early diagnosis is crucial, says Davie. When children with FASD receive appropriate support services and educational programs early on, they have much better outcomes. He believes that early diagnosis and intervention would be a “game-changer” for children born with FASD.
Davie leads five teams engaged in a 5-year international project to find an “epi-code” or epigenetic biomarker for FASD. They are searching for alcohol-induced epigenetic changes in DNA methylation patterns that may signal its presence.
Methylation is an enzymatic reaction that adds a methyl group to DNA. From 60% to 90% of DNA needs to be methylated to work properly. For example, methylation leads to the differentiation of embryonic stem cells into different body tissues. It suppresses the expression of harmful stretches of DNA and is essential in neural development and long-term memory formation. Abnormal DNA methylation is associated with cancer and a host of other diseases.
Recent advances by UBC medical geneticist Dr. Michael Kobor have “set the stage” for early diagnosis of FASD, says Davie. Kobor has identified several genes in buccal (cheek) smears from children with FASD that have subtle changes in DNA methylation.
This work shows “that what we’re doing is realistic and achievable,” says Davie. “It’s really satisfying to know that what we're doing is actually making a difference.”
From laboratory to clinic
Do certain environmental exposures during gestation and early life lead to childhood obesity and possibly type 2 diabetes? That’s a question that Davie would like to answer.
“Environmental exposures experienced very early in the life of children (even in utero) have a big impact on epigenetics and define an individual’s risk for disease. We know that if a mother has diabetes during pregnancy their child is at risk for the development of obesity or type 2 diabetes as they grow up. We’re working towards understanding how diabetes during pregnancy impacts the epigenome of the child at birth and in young adulthood.” he explains.
His team will compare DNA methylation in the umbilical cord blood of newborns as well as white blood cells of normal and obese children to determine the epigenetic changes.
Moving into translational research is a new experience for Davie. He usually works on laboratory research rather than clinical studies. “Venturing into the clinical realm is of real interest to me.”
If Davie and his research team can identify specific epigenetic events, they may be able to develop new biomarkers. If successful, the research could point the way to new approaches to the treatment of obesity and type 2 diabetes.