Tomorrow's Health, Today's Research

Dr. Juan Ausio

Professor, Biochemistry/Microbiology Department
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Phone: (250) 721-8863
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Research area: chromatin assembly and transcription

Research Profile:

Deciphering the histone code

Dr. Juan Ausio wonders if Edgar and Ellen Stedman ever turn in their graves. Just before Watson and Crick uncovered the structure of DNA in the˜50s, people still weren't sure what type of material coded genes; some thought it was DNA, others favoured proteins. The Stedmans proposed that a type of proteins called histones were complex enough to contain a code and an idea that seemed ludicrous once people deciphered the code in DNA.

It turns out this husband and wife team was partially right. In what is now a hot area of research, many researchers believe there is a "histone code" a meta code that controls when and where the underlying DNA code is read.

To back up a little, it may help to understand the structure of chromosomes. While most people are familiar with the double helix, fewer people are familiar with the term "beads on a string".That is how geneticists describe the way the double helix spools around a cluster of histones. The "beads" are DNA wrapped around histones, which are separated by short sections of bare DNA that looks like string. Together the histones and DNA are known as chromatin, which gets further wrapped and compacted to form chromosomes. Genes are only expressed when histones relax their hold on the DNA so that sections of DNA become exposed.

Ausio has never lost faith that histones are important for controlling gene expression, even when most people thought histones were nothing more than a scaffold to pack DNA into cells. Ausio began his work on histones in the '70s during his PhD at the University of Barcelona in his native Spain. At that time, people didn't even know the basic "beads on a string" structure of chromatin, and Ausio admits that only nerds were interested in learning the biophysical techniques needed to solve the structure.

By the time Ausio began studying the structure of chromatin at UVic in 1990, he was interested in changes that occur to histones (they become acetylated) just before genes are read. He wanted to know acetylation plays a role with switching on and off genes.

Using biophysical techniques such as analytical ultracentrifuge and circular dichroism spectroscopy, Ausio uncovered the physical characteristics of chromatin, especially how its stability and structure change when histones are acetylated. He purified and characterized proteins that bind to DNA and histones to figure out if these proteins could be signals for gene expression. He also discovered several histone-like proteins that only show up when sperm are formed. These histone variants pack DNA differently, locking down many genes from being expressed in sperm.

Sometimes it was a lonely field. Few researchers had the patience to stick to what was a tricky problem: histones are relatively homogenous, so how can the cell tell which histones to acetylate? In other words, how does the cell know which histones are associated with which genes?

Everything changed in the mid-'90s when well-known chromatin biologist David Allis realized that transcription factors that bind to DNA, also acetylate histones. Now it’s known that histones can undergo several chemical alterations that act as tags, such as acetylation, phosphorylation, and methylation. These tags can alternate along a tail of 30 amino acids at the end of each histone to give millions of combinations, in other words, a code. The code controls gene expression.

Now researchers talk about “histone writers” referring to the enzymes that tag histones, and 'histone readers'r eferring to proteins that respond to the code. In fact, Ausio says "the histone code could be as important as the DNA code itself".

These days Ausio finds himself at the centre of an exceedingly popular field where most major drug companies are pursuing histone-related therapies. The applications are wide ranging from cancer to almost any other type of genetic disease.

Ausio has also turned to more applied research, looking at the role of histones in prostate cancer and breast cancer: he believes the histone code can go awry telling the cell to express certain genes at the wrong time.

Ausio is also part of a group of Victoria researchers working on Rett syndrome. Rett syndrome is a neural developmental disorder in girls caused by a mutation in MeCP2, a protein that interacts with chromatin. When MeCP2 is mutated it causes genes to turn on abnormally.

Ausio is working with the Medical Genetics department at the Victoria General Hospital to identify different gene mutations involved in Rett syndrome in local patients and study the interactions of this protein with chromatin. They hope to come up with a treatment based on understanding how the mutations disrupt the normal pattern of gene expression.