Controlling genes: MIT says there’s an easier way

MIT researchers show they can turn genes on or off by controlling when DNA is copied into messenger RNA, an advance that could allow scientists to better understand the function of those genes and develop more complex synthetic biology circuits

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CAMBRIDGE, Mass.—Researchers at the Massachuetts Institute of Technology (MIT) have shown that they can turn genes on or offinside yeast and human cells by controlling when DNA is copied intomessenger RNA, an advance that could allow scientists to betterunderstand the function of those genes.

The technique couldalso make it easier to engineer cells that can monitor theirenvironment, produce a drug or detect disease, said Timothy Lu, anassistant professor of electrical engineering and computer science andbiological engineering and the senior author of a paper describing thenew approach in the journal ACS Synthetic Biology.

"I thinkit's going to make it a lot easier to build synthetic circuits," saysLu, a member of MIT's Synthetic Biology Center. "It should increase thescale and the speed at which we can build a variety of syntheticcircuits in yeast cells and mammalian cells."

The new method isbased on a system of viral proteins that have been exploited recentlyto edit the genomes of bacterial and human cells. The original system,called CRISPR, consists of two components: a protein that binds to andslices DNA, and a short strand of RNA that guides the protein to theright location on the genome.

"The CRISPR system is quitepowerful in that it can be targeted to different DNA binding regionsbased on simple recoding of these guide RNAs," Lu says. "By simplyreprogramming the RNA sequence you can direct this protein to anylocation you want on the genome or on a synthetic circuit."

In previous studies, CRISPR has been used to snip out pieces of a geneto disable it or replace it with a new gene. Lu and his colleaguesdecided to use the CRISPR system for a different purpose: controllinggene transcription, the process by which a sequence of DNA is copiedinto messenger RNA (mRNA), which carries out the gene's instructions.

Transcription is tightly regulated by proteins called transcriptionfactors. These proteins bind to specific DNA sequences in the gene'spromoter region and either recruit or block the enzymes needed to copythat gene into mRNA.

For this study, the researchers adaptedthe CRISPR system to act as a transcription factor. First, they modifiedthe usual CRISPR protein, known as Cas9, so that it could no longersnip DNA after binding to it. They also added to the protein a segmentthat activates or represses gene expression by modulating the cell'stranscriptional machinery.

To get Cas9 to the right place, theresearchers also delivered to the target cells a gene for an RNA guidethat corresponds to a DNA sequence on the promoter of the gene they wantto activate.

The researchers showed that once the RNA guideand the Cas9 protein join together inside the target cell, theyaccurately target the correct gene and turn on transcription. To theirsurprise, they found that the same Cas9 complex could also be used toblock gene transcription if targeted to a different part of the gene.

"This is nice in that it allows you do to positive and negativeregulation with the same protein, but with different guide RNAs targetedto different positions in the promoter," Lu says.

The new system should be much easier to use than two other recentlydeveloped transcription-control systems based on DNA-binding proteinsknown as zinc fingers and transcription activator-like effectornucleases (TALENs), Lu says. Although they are effective, designing andassembling the proteins is time-consuming and expensive.

"There's a lot of flexibility with CRISPR, and it really comes from thefact that you don't have to spend any more time doing proteinengineering. You can just change the nucleic acid sequence of the RNAs,"Lu says.

The researchers also designed thetranscription-control system so that it can be induced by certain smallmolecules that can be added to the cell, such as sugars. To do this,they engineered the genes for the guide RNAs so that they are onlyproduced when the small molecule is present. Without the small molecule,there is no guide RNA and the targeted gene is undisturbed.

This type of control could be useful for studying the role of naturallyoccurring genes by turning them on and off at specific points duringdevelopment or disease progression, Lu says.

Lu is now workingon building more advanced synthetic circuits to perform applicationssuch as making decisions based on several inputs from a cell'senvironment. "We'd like to be able to scale this up and demonstrate themost complex circuits that anyone's ever built in yeast and mammaliancells," he says.

The research was funded by the DefenseAdvanced Research Projects Agency, the National Institutes of Health NewInnovator Award and the National Science Foundation.

SOURCE: MIT News Office/Anne Trafton

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