Novel Epigenome Editing Technique Enables Site-Specific Control Over Histone Phosphorylation

Rice University researchers have programmed a modified CRISPR/Cas9 complex to target specific histones with pinpoint accuracy. The study was published in Nature Communications.

"Histones can display an exquisitely diverse spectrum of chemical modifications that serve as beacons or regulatory markers and tell which genes to turn on, and when, and how much to do so," lead researcher Isaac Hilton said. "One of these mysterious modifications is phosphorylation, and we aimed to better illuminate the mechanism by which it can rapidly turn human genes on and off."

No other epigenome editing technique has enabled site-specific control over histone phosphorylation, he said. The programmable Rice tool, called dCas9-dMSK1, fuses a deactivated "dCas9" protein and a "hyperactive" human histone kinase, an enzyme that catalyzes phosphorylation.

The researchers used dCas9-dMSK1 to uncover novel genes and pathways that are pivotal for drug resistance. The team used it to identify three genes previously linked to melanoma drug resistance. "And then she identified seven new genes linked to melanoma resistance," Hilton said. "It's an exciting finding that we are following up on."

"Histone proteins that wrap up DNA can have all sorts of chemical marks and combinations on them," he said. "This results in what has been dubbed a histone code, and one of our goals is to work to decipher it."