microRNAs (miRNA), non-coding RNA molecules, are widely known for regulating mRNA stability and translation. miR-10b has been increasingly implicated in the pathogenesis of gliomas, cancers of the brain. Given the therapeutic potential of targeting miR-10b, researchers at the Brigham sought to understand the mechanism behind the glioma dependence, often referred to as addiction, on miR-10b.

Using Covalent Ligation of Endogenous Argonaute-bound RNAs and subsequent RNA sequencing (CLEAR-CLIP), which enables an unbiased identification of miRNA targets, researchers discovered a new and unconventional nuclear function for miR-10b. They found that it interacts with U6 snRNA, a core component of nuclear spliceosomal machinery, resulting in global splicing alterations within glioma cells and tumors. The work contributes to a growing body of evidence supporting miRNA nuclear localization and subsequent cancer-associated aberrations in gene expression.

Although our data reveals the mechanistic relationships between miR-10b binding to U6, and miR-10b effects on U6 modifications and structure, the molecular mechanisms underlying downstream splicing alterations need to be further investigated. Through this paper, we show an unexpected intersection of the miRNA and splicing machineries and consider this to be an important step toward miRNA-based treatment of cancers."

Anna M. Krichevsky, PhD, Corresponding Author, Department of Neurology, Brigham and Women's Hospital