Researchers at the Weill Institute for Cell and Molecular Biology have uncovered new evidence that two major types of gene-controlling DNA sequences, promoters and enhancers, operate with a shared logic and often perform the same jobs. The finding, made possible through a high-throughput assay they developed called QUASARR-seq, could reshape how scientists design gene therapies, interpret disease-related mutations, and understand cancer genetics.
New research from the lab of Haiyuan Yu, Tisch University Professor of Computational Biology at Cornell University's College of Agriculture and Life Sciences (CALS) and faculty at the Weill Institute, reveals that drawing a distinction between the two classes gene controllers may be too black and white - they seem to respond to the same biological rules and act in concert.
In a study published in Nature Communications on Jan. 30 and led by Mauricio Paramo, a graduate student at the Weill Institute, the team developed a technology capable of measuring an element's promoter and enhancer activity simultaneously, in close collaboration with the lab of John Lis, Barbara McClintock Professor of Molecular Biology & Genetics. This is significant because, until now, most technologies could measure only one function at a time, leaving open the question of whether - and how - the two activities interact inside the same DNA sequence.
Using QUASARR-seq to test thousands of human regulatory elements at once, the group made a surprising discovery: most promoters and enhancers can perform both functions, and they seem to follow a unified regulatory logic rather than behaving as two fundamentally different categories. And together, promoters and enhancers control nearly everything that happens in a cell - how a stem cell becomes a neuron, how the immune system reacts to infection, or how tissues respond to stress. Mutations in either type of element can mis-regulate genes and contribute to diseases from cancer to developmental disorders.
"What we're seeing is that promoters and enhancers draw from the same grammar," Paramo said. "It's not just that they look similar - the same element can perform both functions. That's the key insight."
QUASARR-seq allowed the researchers, for the first time, to measure both types of gene transcription, the genetic copying activity driven by DNA and mRNA. "And at a scale of thousands of activities," Paramo said, "Once we did that, it became clear how tightly these two functions are intertwined."
Another surprising discovery was the presence of a two-way feedback loop. Enhancers activate promoters, as expected - but promoters can also boost the activity of nearby enhancers. This mutual reinforcement could help explain how cells create high-activity "hubs" of transcription during times of stress or differentiation.
"Instead of a one-way street, we're seeing an all-by-all network of regulatory elements influencing each other," Yu said. "That gives us a new framework for understanding - and eventually engineering - gene expression."
The discovery that promoters and enhancers share a unified logic has potentially far-reaching biomedical applications. Current gene therapies rely heavily on engineered promoters and enhancers to control when therapeutic genes turn on. QUASARR-seq could help researchers design dual-function regulatory elements that are more robust, tunable, and predictable across cell types. Because promoter and enhancer strengths are tightly linked, a single engineered change might improve both functions simultaneously, Paramo said.
The study also examined disease-associated mutations in human regulatory elements and found that when a variant disrupts one activity, it almost always disrupts the other. This means that many mutations previously assumed to have mild effects could have broader impacts, impacting both activities at once, Paramo said.
Cancers frequently acquire mutations in promoters and enhancers that rewire gene expression, Paramo said. Dual-function elements help explain why some regulatory mutations lead to aggressive or drug-resistant tumors: a single damaged element may dysregulate its own gene and multiple distant targets.
By revealing that promoters and enhancers operate through a shared regulatory code and can reinforce each other, this research proposes a more unified model of gene regulation - one in which the genome is organized not as isolated switches, but as interconnected regulatory hubs.
This work was supported in part by funding from the National Institutes of Health and Cornell University Center for Vertebrate Genomics Scholarship.
Henry C. Smith is communications specialist for Biological Systems at Cornell Research and Innovation.
