Buried deep inside a cell's nucleus, a genetic switch hunted by biologists for decades has finally been identified. The finding could reveal much about how cells control gene activity, and also illuminate cancer, multiple sclerosis, and other diseases spurred by faulty gene expression.
The newly discovered enzyme acts upon histones, the specialized proteins that strands of DNA loop around. Rather than inert spools, histones are increasingly seen as active cogs in a cell's gene regulation machinery. It's well known, for example, that certain enzymes can add methyl groups to histones, which turns genes either on or off. But many biologists had searched in vain for enzymes that did the opposite, leaving them wondering if these so-called histone demethylases even existed.
Now, Harvard molecular biologist Yang Shi and his colleagues have found a histone demethylase--and they weren't even looking for one. Shi's group had recently focused on a complex of proteins common to lots of species. They homed in on an enzyme in that complex because it could quash gene expression on its own. Biochemistry experiments showing that the enzyme demethylated a specific amino acid, a lysine, on the tail of one kind of histone.
When Shi's group used the technique of RNA interference (RNAi) to reduce levels of the enzyme in human cells, specific histones were methylated and expression of nearby genes increased, the team reported in the 16 December online version of Cell. This, says Shi, drove home that the enzyme, dubbed lysine-specific demethylase 1 (LSD1), represses specific genes by maintaining unmethylated histones.
"It's the sort of thing that everybody wanted to find," says Tony Kouzarides, a molecular biologist at the University of Cambridge, U.K. "It opens up a whole new horizon," adds David Allis of Rockefeller University in New York City.
A report Allis co-authored this fall in Science and a separate paper published at the same time in Cell by Kouzarides's team, offered the first hints that cells could perform demethylation. The two teams independently found that part of a human protein could chemically transform amino acids on a histone, demethylating them in the process. But in those studies, demethylation took place amid other chemical reactions. Shi's paper describes "true demethylation," says Kouzarides.
Several diseases, in particular certain leukemias and colon cancer, have been tentatively linked to faulty methylation, so histone demethylases could represent inviting drug targets.