Dynamic, reversible modifications of DNA and RNA regulate gene expression and transcription, influencing cellular processes, disease development, and organismal health. Small nucleolar RNAs (snoRNAs) are guide RNA molecules that direct chemical modifications to cellular ribosomal RNA (rRNA) targets.
Researchers from the University of Chicago developed a new method for identifying cellular RNA targets of snoRNAs, uncovering thousands of previously unknown targets in human cells and mouse brain tissues. These interactions extend beyond guiding rRNA modifications and include messenger RNA (mRNA), which facilitates protein secretion, an important cellular process.
Chuan He, PhD, co-senior author of the study, stated, "Once you see so many targets for these snoRNAs, you realize there's a lot more to be understood." The findings, published in November 2024 in the journal Cell, suggest significant implications for physiology and potential therapeutic applications.
Despite over 1,000 known genes encoding snoRNAs in the human genome, only about 300 RNA targets had been identified. Many snoRNAs vary in length from 50 to 250 residues, indicating diverse functions. The study utilized a new tool called "snoKARR-seq" to link snoRNAs with their target binding RNAs.
Findings revealed that most newly discovered snoRNA targets do not overlap with known RNA modification sites, suggesting a broader cellular function. Notably, a snoRNA named SNORA73 was found to interact with mRNAs encoding secreted and cell membrane proteins, acting as a "molecular glue" facilitating protein secretion.
The researchers demonstrated that synthetic snoRNA sequences could be engineered to influence protein secretion. By modifying a green fluorescent protein (GFP) reporter to interact with SNORA73, they achieved a 30 to 50% increase in protein secretion.
While the technology for synthesizing and delivering snoRNAs is still under development, He and Pan are optimistic about its potential, especially among various cell types such as neuronal and stem cells. He emphasized the collaborative efforts between the Biological Sciences Division and Physical Sciences Division at UChicago, highlighting the paper as an example of fruitful interdisciplinary research.
Additional authors of the study include Tong Wu, Bernadette A. Miao, Fei Ji, Shun Liu, Pingluan Wang, Yutao Zhao, Yuhao Zhong, Arunkumar Sundaram, Tie-Bo Zeng, Marta Majcherska-Agrawal, and Robert J. Keenan.