Keriayn Smith, PhD, assistant professor in the Department of Genetics at the UNC School of Medicine, is a member of a team of scientists selected to receive a multi-institutional grant from the National Science Foundation after attending an intensive, facilitated workshop called “Dark Dimensions of the RNA Regulome (D2R2).”
The Ideas Lab took place between June 13 – 17, 2022, where participants from a range of disciplines and backgrounds were able to come together and come up with innovative approaches to address major gaps in the field of noncoding RNA.
It was during that five-day workshop when Smith brainstormed with a diverse team of scientists, including Karmella Haynes, PhD, a biomedical engineer from Emory University, Tian Hong, PhD, a computational biologist from the University of Tennessee, Knoxville, and Aaron Johnson, PhD, a molecular geneticist from the University of Colorado Anschutz Medical Campus. Together, they discussed the need to “illuminate the dark matter of the genome.” Alisha Jones, PhD, a chemist from New York University, and Anita Corbett, PhD, a biologist from Emory University, also chimed in to help develop the award-winning proposal.
Smith received $665,786 for four years to further the project.
Our DNA is used as instructions to make coding and non-coding RNA. Whereas coding RNA can make proteins that our bodies will use, non-coding RNA does not encode proteins. Some of these non-coding regions are transcribed to produce long noncoding RNAs (lncRNAs) that are processed similarly to messenger RNAs. Other than that, researchers are unsure about their true functions.
LncRNAs are generally found in low amounts within a cell, and research is just beginning to reveal that they to play a role in a number of biological processes including cell growth, cell identity, environmental interactions, as well as numerous human and animal diseases.
The goal is to understand the mechanisms by which lncRNAs can “silence,” or turn off, large swaths of DNA. And they can do so despite having such low levels of expression in the cell. The foundations of the project will be built upon Xist, a lncRNA that is responsible for silencing one of the X chromosomes in female mammals. To tackle this, the team will test the effects that different arrangements of DNA/RNA code have on the silencing ability in yeast and a mammalian cell culture system.
Smith’s project will computationally predict and experimentally test how lncRNAs control regions of chromosomal DNA in human cells. By engineering lncRNAs to control their activity, scientists will be able to contribute to fundamental understanding of these RNAs and tap into their potential to generate useful biomolecules for agricultural and medical applications.
“From this work, we expect to identify the minimal components and define the levels of non-coding RNA that are required for specific, yet stable epigenetic regulation,” said Smith.
By reconstituting functional components from the ground-up, the team expects to validate, challenge, and/or expand fundamental mechanics involving RNAs. Ultimately, the project will guide the rational design of synthetic systems that can be deployed across mammalian cells. This supports the goal of pushing the boundaries of current understanding of non-coding RNA functions.
“The prospect of tunable non-coding RNA modulation as a tool in biotechnology and bioengineering is particularly exciting,” Smith said.