Shining new light on gene expression

CAMBRIDGE, Mass.—Innovative new technology developed byresearchers from Harvard University and MIT working at the Broad Institute inCambridge, Mass., can rapidly start or stop the expression of any targeted genesimply by shining light on the cells. Employing a technique called optogeneticsthat uses proteins that change function in the presence of light, the team ofresearchers adapted light-sensitive proteins to stimulate or suppress theexpression of a specific gene in response to light.

In this study, the researchers tried targeting nearly 30genes in neurons grown in the lab and in living animals. Using this technique,gene expression could be stimulated or suppressed almost immediately. Thelight-sensitive proteins could be targeted to precisely alter a specificepigenetic marker at a specific location. This ability to precisely controltiming and duration of gene expression is vastly superior to existing methodsof perturbing gene expression.

Professor of bioengineering at Stanford University and oneof the inventors of optogenetics, Dr. Karl Deisseroth, says the most importantinnovation seen in this new technique is its ability to control of genes thatoccur naturally within the cell, rather than relying on manipulating engineeredgenes delivered by scientists. Deisseroth was not part of the research team.

The implications of this new technology are many, but themost immediate applications may be in research focused on learning and memory.The technology should allow researchers to use a beam of light to activate anddeactivate certain processes in animal or human brain cells to see how genesare involved in the process of learning and memory formation.

Another promising area of application may be using thistechnique to study epigenetic changes in cells more broadly. Using thetechnology in conjunction with histone or DNA modification can allowresearchers to precisely alter an epigenetic marker, giving robust insightsinto that marker's function.

"This could allow you to go into the cell and make changesat a specific location to see what the epigenetic marker is doing," says Dr.Feng Zhang, a core member of the Broad Institute and MIT's McGovern Institutefor Brain Research.

The next steps for further research into this emergingtechnology focus on expanding the level of control of gene expression. So far,the technique only uses blue light, but the researchers hope to be able to useother colors of light in the future.

The researchers are now trying to expand the types ofhistone modifiers they can incorporate into the system.

"It would be really useful to expand the number ofepigenetic marks that we can control," said Mark Brigham, a graduate student atthe Harvard School of Engineering and Applied Sciences, in a media releaseabout the research's impending publication. "At the moment, we have a successfulset of histone modifications, but there are a good deal more of them that weand others are going to want to be able to use this technology for."

"We want to be able to change more and different histonemarkers," says Zhang. "We also want to begin to apply this technique tostudying learning, memory and brain function."

Brigham and Silvana Konermann, a graduate student at MIT,are co-lead authors of the paper published in Nature describing the technique. Zhang, an assistantprofessor of neuroscience and biological engineering at MIT, had worked withDeisseroth to develop optogenetics in 2010. This latest research was among thefirst projects on which he and the co-authoring graduate students begancollaborating together in the lab.

The research was funded by a Hubert Schoemaker Fellowship; aU.S. National Institutes of Health (NIH) Transformative R01 Award; an NIHDirector's Pioneer Award; the Keck, McKnight, Vallee, Damon Runyon, SearleScholars, Klingenstein and Simons foundations; and Bob Metcalfe and JanePauley.