A new deep-learning technology can design artificial proteins, called zinc fingers, to bind with any stretch of DNA in the human genome and modify gene expression.
Publishing their research in Nature Biotechnology, scientists at the University of Toronto, Canada, and New York University (NYU) describe ZFDesign, an artificial intelligence technology that is able to model and design zinc finger-DNA interactions tailored to modify any gene's activity. In order to develop ZFDesign, the scientists used data generated from screening nearly 50 billion possible zinc finger-DNA interactions.
'Our program can identify the right grouping of zinc fingers for any modification, making this type of gene editing faster than ever before,' said study lead author Dr David Ichikawa, a former graduate student at NYU.
Zinc fingers are among the most common proteins found in the human body. They often form part of a larger protein molecule and act as a guide to bind to a specific region in the genome to tell the cell how much of a specific protein to make. When this process goes wrong, diseases such as cancer, diabetes and neurodegenerative disorders can occur.
Researchers have long tried to engineer zinc fingers to bind to specific DNA sequences of interest to restore normal epigenetic activity. However, as zinc fingers bind to DNA in complex groups, researchers would need to know how each combination – out of countless possibilities – affect binding to each intended target sequence.
'By speeding up zinc finger design, coupled with their smaller size, our system paves the way for using these proteins to control multiple genes at the same time,' said senior author Dr Marcus Noyes from NYU. 'This approach may help correct diseases that have multiple genetic causes, such as heart disease, obesity, and many cases of autism.'
ZFDesign was tested by using a customised zinc finger to disrupt the coding sequence of a gene in human cells. In order to prove ZFDesign is able to produce zinc fingers capable of making epigenetic changes, they designed zinc fingers to reprogramme transcription factors to bind near a target gene sequence and turn up or down its expression.
The authors hope that human-derived zinc-finger editing will be a safer alternative to CRISPR genome editing, which uses bacterial proteins and thus may trigger an immune response.
'Designing zinc fingers to bind specific DNA targets has been an unsolved problem for decades,' Professor Philip Kim from the University of Toronto said. 'Our work should enable a new generation of in vivo therapeutics, which have proven difficult to develop with CRISPR and other DNA targeting technologies.'
However, the authors caution that zinc fingers can be difficult to control as they are not always specific to a single gene, potentially affect DNA sequences after a particular target, leading to off target effects. In the future they plan to improve ZFDesign to design more precise zinc finger combinations.
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