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Paper Describes Microarrays to Detect DNA Interactions with Zinc Finger Proteins

NEW YORK, June 14 - Microarrays can be used to detect DNA sequences that serve as binding sites for zinc finger proteins, key molecules involved in gene regulation, an article published in this week’s Proceedings of the National Academy of Sciences said.

The article, "Exploring the DNA-binding specificities of zinc fingers with DNA  microarrays ,” describes a project in which researchers from London-based Gendaq, Harvard University, and the UK’s Medical Research Council sought to efficiently characterize lower affinity DNA-zinc finger interactions, as well as the effect of mutations in DNA binding sites on the Zinc Finger-DNA interactions.

They chose microarray technology rather than other methods because it allows a number of interactions to be measured at once, has higher sensitivity, and can be done more cost effectively.

“This technology provides significant cost and time advantages over conventional methods such as gel mobility-shift assays and nitrocellulose-binding assays, which can take months or even years to measure the effects of mutations for a large set of variant DNA-protein interactions,” the authors wrote.

The researchers spotted onto glass slides double-stranded DNA oligonucleotides from numerous possible binding sites for a specific zinc finger protein, the mouse transcription factor Zif268. They chose this transcription factor as a means to test the microarray technology because its interaction with DNA has already been well characterized through crystallography, but specific information about the sequence to which it binds preferentially had not previously been elucidated.

Using this method, researchers were able to determine the sequences to which the transcription factors preferentially bind. They were also able to learn about the binding patterns of mutant transcription factors.

Gendaq sought to detect the zinc finger-DNA interactions as part of its efforts to develop its marquis product, the Z-switch. The Z-switch is a lab-engineered zinc finger protein that allows any gene in a eukaryotic cell to be up- or down-regulated.  

“These DNA  microarrays  allow us to evaluate comprehensively the specificity and affinity of our engineered zinc fingers in a matter of hours,” Yen Choo, Gendaq’s chief scientific officer and an author of the paper, said in a statement. “Our interest in developing this  microarray  method underlies our commitment to produce zinc finger proteins of the highest quality, and to do so using high-throughput methods.”

The technology the researchers used could make possible arrays that test all possible gene promoters against transcription factors or other proteins under different conditions, Choo said.

Gendaq, which Sangamo Biosciences recently obtained the option to acquire in a stock deal worth $39.7 million, is a privately held offshoot of the Medical Research Council’s Laboratory of Molecular Biology in Cambridge, UK. The company was assigned the intellectual property for the Lab’s zinc finger technology, and has been commercializing this technology as the Z-switch.

In addition to the most recent paper, Gendaq has published two previous papers in PNAS that describe the science behind its technology. The two papers, which appeared in February, outlined new methods of constructing improved zinc finger protein multimers, biomolecules that bind to DNA sequences with high specificity. Gendaq uses these multimers to make Z-switches.    
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