Research says epigenetic control coming
Bio-engineers have developed a method to precisely control when genes are turned on and active.
The mind-boggling new technology allows researchers to turn on specific gene promoters and enhancers - parts of the genome that control gene activity - by chemically manipulating proteins that package DNA.
The protein packing that supports and controls gene activity is known as the epigenome.
The team from Duke University in the US says having the ability to steer the epigenome will help them explore the roles that different DNA influences play in cell fate or the risk for genetic disease.
“The epigenome is everything associated with the genome other than the actual genetic sequence, and is just as important as our DNA in determining cell function in healthy and diseased conditions,” said Charles Gersbach, assistant professor of biomedical engineering at Duke.
“That becomes immediately obvious when you consider that we have over 200 cell types, and yet the DNA in each is virtually the same. The epigenome determines which genes each cell activates and to what degree.”
“Next to every gene is a DNA sequence called a promoter that controls its activity,” explained Gersbach.
“But there's also many other pieces of the genome called enhancers that aren't next to any genes at all, and yet they play a critical role in influencing gene activity too.”
The epigenome editing application uses a silenced form of the common DNA-cutting mechanism CRISPR.
CRISPR was re-purposed as a targeting system to deliver an enzyme (acetyltransferase) to specific promoters and enhancers.
The artificial epigenetic agent was tested by targeting a few well-studied gene promoters and enhancers.
To the researchers’ great surprise, not only did the agent activate the gene promoters, it turned on the adjacent genes better than their previous methods.
Equally surprising was that it worked on enhancers as well: they could turn on a gene - or even families of genes - by targeting enhancers at distant locations in the genome, something that their previous gene activators could not do.
The team says the test revealed an emerging ability to probe millions of potential enhancers in a way never before possible.
“Some genetic diseases are straightforward - if you have a mutation within a particular gene, then you have the disease,” said Isaac Hilton, postdoctoral fellow in the Gersbach Lab and first author of the study.
“But many diseases, like cancer, cardiovascular disease or neurodegenerative conditions, have a much more complex genetic component.
“Many different variations in the genome sequence can affect your risk of disease, and this genetic variation can occur in these enhancers... where they can change the levels of gene expression.
“With this technology, we can explore what exactly it is that they're doing and how it relates to disease or response to drug therapies.”
The research report - Epigenome editing by a CRISPR-Cas9-based acetyltransferase activates genes from promoters and enhancers – will appear in the journal Nature Biotechnology.