RETHINKING “THE CODE”

A decade ago, gene expression seemed so straightforward: Genes were either switched on or off. Not both. Then in 2006, a blockbuster finding reported that developmentally regulated genes in mouse embryonic stem cells can have marks associated with both active and repressed genes, and that such genes, which were referred to as “bivalently marked genes,” can be committed either way during development and differentiation.

This paradoxical state—akin to figuring out how to navigate a red and green traffic signal—has since undergone scrutiny by labs worldwide. When a team led by Investigator Ali Shilatifard, PhD, revisited that notion, the researchers not only identified the protein complex that implements the activating histone mark specifically at “poised” genes in mouse embryonic stem (ES) cells, but also found that its loss has little effect on developmental gene activation during differentiation. This suggests there is more to learn about interpreting histone modification patterns in embryonic and even cancer cells.

“There has been a lot of excitement over the idea that promoters of developmentally regulated genes exhibit both the stop and go signals,” explains Shilatifard. “That work supports the idea that histone modifications could constitute a code that regulates gene expression. However, we have argued that the code is not absolute and is context dependent.”

The study’s findings also potentially impact oncogenesis, as tumor-initiating cancer stem cells exhibit bivalent histone marks at some genes. “Cancer stem cells are resistant to chemotherapy, making them difficult to eradicate,” says postdoctoral fellow and the study’s first author Deqing Hu, PhD. “Our work could shed light on how cancer stem cells form a tumor or suggest a way to shut these genes down.”

The study was published in the August 2013 issue of Nature Structural and Molecular Biology.