New images of an enzyme in action as it interacts with the chromosome could provide important insight into how cells — including cancer cells — regulate their genes. The enzyme, LSD1, can “turn off” gene expression by removing chemical flags (methyl groups) from the nucleosome — tightly packed units of DNA and protein in chromosomes. The LSD1 histone demethylase is over-expressed in multiple cancer types, resulting in disruption to normal cell development, and the new structure could inform therapeutic interventions that target the enzyme.
A paper by Penn State researchers describing the crystal structure of the LSD1-nucleosome complex was published in the journal Molecular Cell and also explains the previously unclear but important role of a separate accessory protein, CoREST. The research team found that LSD1 unexpectedly binds outside of the core of the nucleosome, where most activities on the nucleosome take place. LSD1 instead binds to DNA that extends away from the core, and CoREST acts as an intermediary, binding to both the nucleosome core and to LSD1.
The structure also explains how the CoREST accessory protein enables LSD1 to work on nucleosomes. The researchers believe that the LSD1-CoREST system could serve as a model for how other accessory proteins target chromatin enzymes to nucleosomes. The research team also investigated a version of the LSD1 enzyme with a mutation believed to render it inactive. Such inactive mutants have been used to test the effects of eliminating LSD1’s activity in cells. However, the team found that the mutant is actually active in the presence of the nucleosome.
The research team identified other LSD1 mutations that are inactive in the presence of the nucleosome and recommends using these in future studies that require inactive mutants.
