Researchers find a way to pull the genomic puppetmaster's strings
It could provide a new avenue for gene therapies and guiding stem cell differentiation
Researchers at Duke University in Durham, NC in the US have developed a new method to control precisely when genes are turned on and active.
The technology allows scientists to turn on specific gene promoters and enhancers – pieces of the genome that control gene activity – by chemically manipulating proteins that package DNA. This group of biomolecules that supports and controls gene activity is known collectively as the epigenome.
The team says having the ability to steer the epigenome will help it explore the roles that particular promoters and enhancers play in cell fate or in risk for genetic disease. It could also provide a new avenue for gene therapies and guiding stem cell differentiation.
The study appears online in the journal 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.
This 'genetic puppetmaster' consists of DNA packaging proteins called histones and a host of chemical modifications that help determine whether a gene is on or off. But the researchers did not have to modify the genes themselves to gain some control.
I wanted to develop tools to go in and modify very specific epigenetic marks in very specific places
'Next to every gene is a DNA sequence called a promoter that controls its activity,' said Gersbach. 'But there are 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.'
Timothy Reddy, Assistant Professor of Biostatistics and Bioinformatics at Duke, has spent almost 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.
To activate these enhancers and see what they do, Reddy thought he could chemically alter the histones at the enhancers to turn them on.
'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,' he said.
Reddy found that specificity by teaming up with Gersbach, who specialises in the CRISPR gene-targeting system, which is used to cut and paste DNA sequences in the human genome.
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 was not clear if they were enough to turn genes on.
Not only did the agent activate the gene promoters, but it also 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 the enhancers that Tim has identified. 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.'
