A new research center led by UChicago scientists will develop unprecedented technologies to decode RNA modifications, the next layer of gene expression control. The $10.6 million, five-year award from the National Human Genome Research Institute will establish Chicago’s first Center of Excellence in Genomic Science—one of only seven such centers in the United States.
The center, led by Chuan He, the John T. Wilson Distinguished Service Professor in Chemistry and Howard Hughes Medical Institute Investigator, will create new technologies for studying how RNA—the middle step between DNA and protein—is regulated by chemical modifications inside cells. These modifications, present in almost every eukaryotic organism and cell, are critical in development and disease, including neurological disorders and cancer.
“In the next five years, both the NIH and us envision that this CEGS will invent new technologies to really impact fundamental biology and human health,” He said. “RNA modifications are one of the major ways to affect gene expression regulation; they intersect with different biological pathways and impact essential and fundamental biological processes. So we want to solve the current bottleneck problems of their detection and sequencing.”
In cells, DNA encodes the recipe for producing proteins, the building blocks of life. The middleman is RNA, a copy of a DNA segment that travels to ribosomes, where proteins are constructed. While much research has focused on DNA modifications that stimulate or inhibit this gene expression, the impact of RNA modifications in gene expression received scant attention until 2011.
At that time, He’s laboratory discovered the first RNA demethylase and demonstrated the first example of reversible RNA modification that could affect gene expression, inspiring a new branch of biology. At least two RNA modifications, N6-methyladenosine, or m6A, and N1-methyladenosine, or m1A, are now known to be reversible and significantly affect gene expression. Proteins that add, remove or recognize these chemical groups on RNA have been identified and characterized in recent years and the field has expanded at a rapid pace.
But as interest in these elements grew, researchers discovered the limitations of current approaches for finding and mapping RNA modifications, as well as determining their roles in development and disease. The new center’s primary mission will be to develop new methods and sequencing technologies that enable fundamental and clinical investigations of various chemical marks on RNA or epitranscriptomes, facilitating the discovery and characterization of new “switches” on the control panel of gene expression in different biological processes and disease.
“Biological discoveries are often driven by the development of enabling technologies,” said CEGS co-director Tao Pan, professor in biochemistry and molecular biology. “Our new technologies should also be useful for disease diagnostics and help future development of therapeutic agents targeting RNA modification pathways.”
The new center will pursue new procedures for finding and mapping RNA modifications, as well as manipulating their functions to observe their effects upon RNA metabolism and gene expression. The team also will develop new bioinformatics methods for analyzing RNA modifications. Collaborations with researchers at Johns Hopkins University and Emory University will apply these new technologies to studies of human neurodevelopment and neurogenesis, to examine the role of RNA modifications in brain development and disease.
Besides boosting international research in this frontier area, the center also will stimulate UChicago research across several departments. Co-investigators Pan and Bryan Dickinson, assistant professor in chemistry, will work with He’s group on technology development, while researchers from the Department of Human Genetics will lead the bioinformatics arm of the initiative.
Additionally, campus research on the biological and medical significance of RNA modifications will benefit from the new technologies as they are tested and released. Several UChicago laboratories have already begun studying the effects of these regulators in several domains, He said, including neurobiology and memory, various human cancers, energy metabolism, virus infection, immune system development and embryo development.
“Hopefully, this will boost genomics and RNA biology research on campus,” He said. “It's a very unique, true PSD/BSD collaboration, a combination of nucleic acid chemistry, biochemistry, genomics, with RNA biology. I think this center will further foster interdisciplinary collaborations.”