Scientists at the Whitehead Institute report the discovery of a set of 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 transitions such as that from embryonic stem cell to nerve cell. However, cancer cells are able to assemble their own 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 Richard Young, a member of the Whitehead team. “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. Furthermore these special controls are hijacked in cancer and other diseases.”

The findings are described in dual papers from Dr. Young and collaborators at the Dana-Farber Cancer Institute published together in today’s edition of Cell.

In the first work, the Young lab established 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 research, including that of the recently described ENCODE (Encyclopedia of DNA Elements) project, has 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, noted Dr. Young, but he and his colleagues say they have found something of a shortcut to solving the core gene control circuitry. They show that only a few hundred special switches, i.e., super-enhancers, control the key genes that actually make each cell different.

“What is fantastic about this concept is its simplicity,” added Denes Hnisz, Ph.D., 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.”

Dr. Young said 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,” he pointed out, noting that “the discovery of super-enhancers promises to help us solve the regulatory circuitry of all human cells. That includes cancer cells.”

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