Observatory scientists will build models to predict the function of all regulatory elements in the human genome and collate an atlas for genome science and medicine
The Broad’s new Gene Regulation Observatory will take the most detailed look yet at the non-coding genome
The initial sequencing of the human genome revealed that only 1% of human DNA encodes protein. The other 99% was once thought to be mostly “junk DNA,” but over the past 15 years, Broad scientists have led work showing that rather than mere filler, the non-coding genome contains crucial regulatory elements, or bits of DNA that control the activity of genes.
ENCODE, the Human Cell Atlas, GTEx, and many other projects have catalogued millions of noncoding elements and provided tantalizing insight relating them to genes, cell states, and disease. Other studies have suggested that most genetic risk factors for common disease reside within or near non-coding regulatory elements. But for the vast majority of elements, it’s unclear what these elements do, when they are active, how they operate on genes, pathways, and circuitry, and how they regulate cellular activities or lead to disease.
To learn more about the function of these non-coding regions, researchers at the Broad met informally during the summer of 2020 to brainstorm solutions. Mere months later, they launched the Gene Regulation Observatory (GRO), with the goal of building the most detailed map yet of the non-coding genome, one with base-level resolution and deep functional information. The map will help scientists interpret disease risk factors, explain how the body’s hundreds of cell types arise, and inform efforts to engineer cells in targeted ways.
“Decoding the genome’s regulatory elements and circuits is a priority for the Broad Institute,” said Todd Golub, director of the Broad Institute. “With its ambitious goal to produce such a detailed atlas, the Gene Regulation Observatory will enable scientists across the institute and beyond to more fully explore crucial biomedical questions.”
The GRO serves as a scientific hub, bringing together experts in gene regulation and genome biology, genome editing, cell circuitry, and more from across the Broad community. Their aim is to assemble a foundational base of data on all the genome’s regulatory elements, transcription factors, genome structures, and the gene regulatory circuits that direct cell state. The data will inform computational models that predict the function of each base in different cell types or disease settings.
“The Gene Regulation Observatory will go beyond a simple list of the millions of regulatory elements, to build models that encompass their functions and connectivities,” said Brad Bernstein, GRO’s leader, Broad institute member, and professor in pathology at Massachusetts General Hospital and Harvard Medical School.
As the atlas grows, the GRO will partner with experts in data science and machine learning to integrate these data and iterate towards more precise computational models, which can generate predictions about the impact of genetic variants.
The models, he explained, will allow geneticists to more easily explore how genetic variants cause disease. Their predictions can generate testable hypotheses about what the variants are doing, which genes they target, where they exerts effects in the body, and where there are opportunities for therapeutic intervention.
To achieve their vision, the scientists are first assembling a community of experts in genome biology, function, and architecture, to initiate flagship projects that will generate foundational data in a small number of cell types. They’ll use experimental approaches developed at the Broad and elsewhere, such as single-cell technologies, genome and epigenome editing, and high-throughput perturbations to investigate regulatory elements and probe their biological effects. The GRO will also seek partnerships with the Broad’s experts in areas such as cancer, psychiatric disease, and immunology, to incorporate disease-relevant cell types and research questions.
“It’s a great time to do this science because the technologies are ready and the community is ready,” said Liz Gaskell, associate director of the GRO. “We have the parts list, and now it’s time to discover how all those pieces fit together and what they do.”