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Pulling the genomic puppet
master’s strings
04-05-2015
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DURHAM, N.C. -- Duke researchers have developed a new method to precisely control when genes are turned on and
active. The new technology allows researchers to turn on specific gene promoters and enhancers—pieces of the genome that control gene activity—by
chemically manipulating proteins that package DNA, the web of biomolecules collectively as the epigenome.
The
researchers say having the ability to steer the epigenome will help them explore the roles that particular promoters and enhancers play in cell fate or the
risk for genetic disease, and it could provide a new avenue for gene therapies and guiding stem cell differentiation. The study appears online April 6 in Nature Biotechnology.
“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 in a news
release. “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.”
This genetic puppet master
consists of DNA packaging proteins called histones and a host of chemical modifications—either to these histones or the DNA itself—that help
determine whether a gene is on or off.
But Gersbach's team didn't have to modify the genes themselves to
gain some control. “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.”
Timothy Reddy, assistant professor of biostatistics and bioinformatics at
Duke, has spent the better part of a decade mapping millions of these enhancers across the human genome. There has not, however, been a good way to find out
exactly what each one does. An enhancer might affect a gene next door or several genes across the genome or maybe none at all.
To activate these enhancers and see what they do, Reddy thought perhaps he could chemically alter the histones at the
enhancers to turn them on.
“There are already drugs that will affect enhancers across the whole genome, but
that’s like scorching the earth,” said Reddy. “I wanted to develop tools to go in and modify very specific epigenetic marks in very
specific places to find out what individual enhancers are doing.”
Reddy found that specificity by teaming up
with Gersbach, his neighbor within Duke’s Center for Genomic and Computational Biology, who specializes in a gene-targeting system called CRISPR.
Originally discovered as a natural antiviral system in bacteria, researchers have hijacked the system over the past few years and are now using it to cut and
paste DNA sequences in the human genome.
For this epigenome editing application, Gersbach silenced the DNA-cutting
mechanism of CRISPR and used it solely as a targeting system to deliver an enzyme (acetyltransferase) to specific promoters and enhancers.
“It’s like we use CRISPR to find a genetic address so that we can alter the DNA’s packaging at that
specific site,” said Reddy.
Gersbach and Reddy put their artificial epigenetic agent to the test by
targeting a few well-studied gene promoters and enhancers. While these histone modifications have long been associated with gene activity, it wasn’t
clear if they were enough to turn genes on. And though Gersbach and Reddy had previously used other technologies to activate gene promoters, they had not
successfully activated enhancers.
To the duo’s 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.
But the real excitement from their results is 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 that Tim has identified, 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.”
Gersbach added, “Not only can you start to answer those questions, but you might be
able to use this technique for gene therapy to activate genes that have been abnormally silenced or to control the paths that stem cells take toward becoming
different types of cells. These are all directions we will be pursuing in the future.”
This work was
supported by the National Institutes of Health and the National Science Foundation.
Code: E04031501 Back |
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