Public release date: 11-Apr-2013 [ | E-mail | Share ]

Contact: Matt Fearer fearer@wi.mit.edu 617-452-4630 Whitehead Institute for Biomedical Research

CAMBRIDGE, Mass. (April 11, 2013) In a surprising finding that helps explain fundamental behaviors of normal and diseased cells, Whitehead Institute scientists have discovered a set of powerful gene regulators dubbed "super-enhancers" that control cell state and identity. Healthy cells employ these super-enhancers to control genes responsible for cellular functions and developmental transitionssuch as that from embryonic stem cell to nerve cellbut cancer cells are able to assemble their own insidious super-enhancers to overproduce harmful oncogenes that lead to aggressive tumors.

"We have been marveling at the complexity of cellular control, with millions of enhancers controlling tens of thousands of genes in the vast array of cells that comprise human beings," says Whitehead Member Richard Young. "So it was a surprise to find that only a few hundred super-enhancers control most key genes that give each cell its special properties and functions, and furthermore, that these special controls are hijacked in cancer and other diseases."

The findings are described in dual papers from Young and collaborators at Dana-Farber Cancer Institute published together in the April 11 edition of the journal Cell.

In the first work, the Young lab establishes a model of gene regulation in normal cells that appears to be dramatically less complex and more solvable than previously thought. To date, a vast body of researchincluding that of the recently described ENCODE (Encyclopedia of DNA Elements) projecthas identified more than one million enhancers or "switches" that control gene expression in mammalian cells. Deciphering the precise function and target gene for each of these switches will be a daunting task, but Young and colleagues have found something of a shortcut to solving the core gene control circuitry. They show that only a few hundred special switchesthat is, super-enhancerscontrol the key genes that actually make each cell different.

"What is fantastic about this concept is its simplicity," notes Denes Hnisz, a Young lab postdoctoral scientist and a co-author of the first Cell paper. "We found that genes that are especially important for each cell are regulated by these specialized enhancers. But we also discovered that the super-enhancers are especially quick to change during development, and thus loss of old super-enhancers and establishment of new ones drives cell identity changes during development."

Young says such changes in cell identity probably begin and end with the super-enhancers, which, though powerful, are also exquisitely sensitive to alterations in their environment. In fact, as differentiation begins, active super-enhancers are decommissioned, leading to changes in gene expression programs that fall under the control of newly established super-enhancers. It's a process that adds remarkable insight to our understanding of how a fertilized egg eventually gives rise to the more than one trillion cells of the human body.

"The discovery of super-enhancers promises to help us solve the regulatory circuitry of all human cells," Young says. That includes cancer cells.

While mapping the locations of super-enhancers along the genome of multiple myeloma (MM) cells, which are especially aggressive blood cancer cells, Young lab scientists found them in areas associated with known cancer-causing genes, including the notorious MYC oncogene. It turns out these MM cells were forming their own super-enhancers to drive dangerous overexpression of their oncogenes. Moreover, this phenomenon was not limited to MM cells, as the researchers identified super-enhancers at key tumor genes in small-cell lung cancer and the brain cancer glioblastoma multiforme.

Read more:
Genetic master controls expose cancers' Achilles' heel

Comments are closed.