A set of powerful gene regulators that control cell identity in a few mouse and human cell types is being recently discovered.
Whitehead Institute scientists are now showing that these regulators—which they named "super-enhancers"—act across a vast array of human cell types and are enriched in mutated regions of the genome that are closely associated with a broad spectrum of diseases.
The findings, published online today by the journal Cell, suggest that these super-enhancers, first described in Cell several months ago by Whitehead Member Richard Young, could ultimately play important roles in disease diagnostics and therapeutics.
"We've gone from a few cells to a broad swath of human cell types to create this resource and make it available to the biomedical research community," says Young, who is also a professor of biology at MIT.
Young notes that the striking finding of the new study is that beyond their roles in control of healthy cells, super-enhancers are involved in regulating the function—and dysfunction—of diseased cells.
"We were surprised that for so many different diseases, mutations associated with the disease occur in super-enhancers" says postdoctoral scientist Brian Abraham, an author of the study. Indeed, he and other researchers in Young's lab found in disease-relevant cell types genetic mutations associated with Alzheimer's disease, diabetes, and many autoimmune diseases in genomic regions under the control of specific super-enhancers.
The researchers also found super-enhancers operating in particularly insidious fashion across a broad spectrum of cancers, observing cancer cells assembling their own super-enhancers to overproduce malevolent oncogenes that drive such cancer hallmarks as hyperproliferation, invasion, and metastasis. Young believes that identifying, mapping, and disrupting super-enhancers could alter the way cancers are managed in the clinic.
"When we focus on personalized medicine for cancer patients, super-enhancers could serve as useful biomarkers for tracking and understanding the evolution of a person's cancer," says Young. "Ultimately, super-enhancers may well become important targets for therapeutic intervention."
This work was supported by grants from the National Institutes of Health (grants HG002668, CA109901, and CA146445).