RNA-centric mechanism regulates microRNAs linked to cancer, neurological disorders

MicroRNAs, also known as miRNAs, are small, evolutionarily conserved noncoding RNAs—that is, bits of genetic code that act as key gene regulators in various aspects of biological processes that are significant for human health.

Qi Zhang, PhD. Image Credit: University of North Carolina Health Care.

miRNAs are tightly controlled because of their crucial roles in gene regulation, and abnormal expressions of miRNA have been associated with cardiovascular diseases, neurological disorders, cancer, and other diseases.

The focus of the intense recent study was to understand the regulation of miRNAs. Over the years, researchers have identified numerous protein regulators of miRNA biogenesis cellular routes, and it is generally believed that such protein factors act on predominantly passive miRNA processing intermediates to guide their maturation.

The laboratory of Qi Zhang, Ph.D., associate professor in the Department of Biochemistry and Biophysics at the University of North Carolina Health Care (UNC), has now identified a new RNA-centric mechanism through which miRNA processing intermediates can have direct, vital roles to play in the regulation of miRNA biogenesis.

Published in the Nature Chemical Biology journal, the latest findings reveal a “hidden” layer of regulation through which the inherent dynamic ensemble of miRNA processing intermediates can guide the outcome of key biological processes in response to cellular and environmental stimuli in the absence of protein factors. But if these processes go awry, it could lead to various diseases. The most crucial step for identifying new ways to better therapeutics is to understand the role of miRNAs in numerous diseases.

microRNA-21 (miR-21) plays a role in the creation, development, and metastasis of cancerous tumors, and it is also involved in the survival of cells. When Zhang’s laboratory examined miR-21 using NMR relaxation dispersion—a sophisticated imaging method that can detect thinly populated transient states that frequently evade traditional detection methods—they observed that miR-21 precursor occurs as an ensemble of dynamic conformational states, which is unexpectedly responsive to the environment’s acidity.

The researchers found that, across physiological conditions, around 1%–15% of the miR-21 precursor carries an extra proton—the smallest chemical modification called protonation. This protonated state has a lifespan of around 0.8 ms and sequesters a crucial residue into a novel structure that considerably improves the efficiency of processing the miR-21 precursor into mature miR-21.

Through these robust “imaging” methods, investigators can now reveal the transient states of RNAs as the “hidden” layers of regulation, including a brief riboswitch state that is significant in regulating gene transcription—a state discovered by the Zhang laboratory in 2017.

We think these techniques add more promise for new strategies to create RNA-targeted therapeutics. And that is our goal; we need better targeted therapies for many diseases including cancers.”

Qi Zhang, PhD, Associate Professor, Department of Biochemistry and Biophysics, University of North Carolina Health Care

Zhang is also a member of the Lineberger Comprehensive Cancer Center at the University of North Carolina Health Care.