Modification of messenger RNA by 2′-O-methylation regulates gene expression in vivo

Olga Ilkayeva, Ph.D., is the Director of the Metabolomics Core Laboratory at Duke Molecular Physiology Institute. She received her Ph.D. training in Cell Regulation from UT Southwestern Medical Center at Dallas, TX. Her postdoctoral research in the laboratory of Dr. Chris Newgard at Duke University Medical Center focused on lipid metabolism and regulation of insulin secretion. As a research scientist at the Stedman Nutrition and Metabolism Center, Dr. Ilkayeva expanded her studies to include the development of targeted mass spectrometry analyses. Currently, she works on developing and validating quantitative mass spectrometry methods used for metabolic profiling of various biological models with emphasis on diabetes, obesity, cardiovascular disease, and the role of gut microbiome in both health and disease.

The Holley Laboratory is focused on the role of non-coding RNA (ncRNA) in cardiovascular health and disease, with a special emphasis on snoRNA (small nucleolar RNA).  snoRNAs are canonically known to guide the chemical modification of other RNAs, with ribosomal RNA being the primary target.  Dr. Holley’s research has helped to uncover a novel biologic role for the Rpl13a snoRNAs in the regulation of reactive oxygen species (ROS) and oxidative stress.  These four snoRNAs (U32a, U33, U34, and U35a) have a critical role in the oxidative stress response to a variety of stimuli, including saturated fatty acids, lipopolysaccharide, doxorubicin, and hydrogen peroxide.

The Holley Lab has shown that at least one mechanism linking the Rpl13a snoRNAs to ROS and oxidative stress is snoRNA-guided methylation of mRNA. This methylation in an mRNA coding sequence inhibits subsequent protein translation. We have also shown that snoRNA-guided methylation alters RNA conformational ensembles, which can stabilize short-lived structures.

Currently, the lab is studying the role of Rpl13a snoRNAs in atherosclerosis, where loss or inhibition of these snoRNAs reduces athero by ~50%. We are actively pursuing translational research opportunities to design "RNA therapeutics" targeting these snoRNAs for potential clinical use.