Experimental cancer treatments that harness souped-up segments of DNA called super-enhancers to activate genes are working their way to the clinic for the first time. But scientists are still debating how these elements work — and whether they represent a fundamentally new way of regulating genes.
Screening for a particular super-enhancer can identify people with acute myeloid leukaemia who might benefit from a drug called tamibarotene, suggest preliminary data presented by the drug’s maker, Syros Pharmaceuticals, on 2 December at a meeting of the American Society of Hematology in San Diego, California. And on 15 November, the company debuted data from another preliminary trial, in which patients with solid tumours were given a drug that targets a protein called CDK7. Laboratory tests have shown1 that inhibiting this protein can reduce activity of a super-enhancer that has been linked to some cancers.
The trials are the first attempts to target super-enhancers to treat human disease. But it is still unclear whether these DNA segments are truly stronger versions of better-known gene-regulating sequences called enhancers. “The word is still out,” says Lothar Hennighausen, a geneticist at the US National Institute of Diabetes and Digestive and Kidney Diseases in Bethesda, Maryland. “I’m inclined to think that they are not.”
Researchers have long known that enhancers are important for regulating when and how strongly genes are expressed. But in 2013, researchers found2 that some enhancers, called super-enhancers, cluster together near genes that help to determine a cell’s unique identity — whether it becomes a mammary or a muscle cell, for instance.
Form vs. function
Super-enhancers seem to be particularly important in embryonic stem cells, and they are sometimes hijacked by cancer cells to drive the aberrant gene activity that fuels tumour growth.
And super-enhancers also attract unusually large numbers of the proteins required to activate the genes they control. These clusters of enhancers and proteins might allow cells to tightly regulate important genes, ensuring that they will be turned on exactly when needed and in precisely the right amount, says Christopher Vakoc, who studies gene expression at Cold Spring Harbor Laboratory in New York and has advised Syros.
“It’s all about precision,” says Vakoc. “When the cell goes to that much effort to control a gene, it’s because the product of that gene is pivotal in biology.”
Although mammalian cells have thousands of enhancers, they typically have only a few hundred super-enhancers. As a result, researchers now use super-enhancers as a signpost for important genes, says Hennighausen. Understanding how they work could shed light on how cells adopt their identities. But researchers don't know whether the enhancers in a cluster act independently, or whether they work synergistically in a new form of gene regulation.
That question arose right from the start, says Richard Young, a biologist at the Whitehead Institute for Biomedical Research and a co-founder of Syros — both in Cambridge, Massachusetts. “There were investigators who questioned whether or not they should have the term ‘super’, because it implied some function that typical enhancers didn’t have,” he says. “To be frank, at the time we didn’t know if they had some special function.”
Since then, researchers have scrutinized a few super-enhancers, studying the function of each individual enhancer in the cluster. But the results are inconclusive: some enhancers show signs of working together, whereas others seem to work independently. “It’s a very intense debate,” says Denes Hnisz, a molecular biologist at the Max Planck Institute for Molecular Genetics in Berlin.
Hnisz notes that the discrepancy might arise in part from the algorithms used to identify enhancers in genomic data: the algorithms could be mislabelling some sequences as super-enhancers. And different labs use different assays to test for super-enhancer activity, he adds, which could introduce another source of conflict.
Resolving the debate might have to wait until more scientists have studied more super-enhancers, says Douglas Higgs, a haematologist at the University of Oxford, UK. Only a handful of these DNA segments have been analysed in detail, he says. “At the current time, it is hard to be sure if they represent a new type of fundamental regulatory element.”
For Syros, the debate is largely academic, says Nancy Simonian, the company’s president and chief executive. “From our point of view, it doesn’t really matter,” she says. “We’re just saying it’s a marker for a hotspot that we know is associated with genes that are really important for controlling the cell.”
The next few years could bring some answers. Studies of enhancers fell out of favour in the early 2000s, says Hennighausen. But technological advances are bringing them back into fashion. The ability to use relatively simple gene-editing tools, such as CRISPR–Cas9, to alter enhancer sequences has made it easier to study their function, he notes. An experiment that once took two years can now be done in a few months, and for significantly less money.
“The questions were always there, but the technology was needed to answer them,” he says. “The whole field is emerging right now.”
Nature 564, 173-174 (2018)