mRNA splicing is modulated by intronic microRNAs

Luba Farberov; Daphna Weissglas-Volkov; Guy Shapira; Yazeed Zoabi; Chen Schiff; Barbara Kloeckener-Gruissem; John Neidhardt; Noam Shomron

doi:10.1016/j.isci.2023.107723

mRNA splicing is modulated by intronic microRNAs

iScience. 2023 Aug 28;26(10):107723. doi: 10.1016/j.isci.2023.107723. eCollection 2023 Oct 20.

Authors

Luba Farberov¹, Daphna Weissglas-Volkov^{1

2}, Guy Shapira^{1

2}, Yazeed Zoabi^{1

2}, Chen Schiff¹, Barbara Kloeckener-Gruissem^{3

4}, John Neidhardt^{5

6}, Noam Shomron^{1

2

7}

Affiliations

¹ Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.
² Edmond J. Safra Center for Bioinformatics, Tel Aviv University, Tel Aviv, Israel.
³ Institute of Medical Molecular Genetics, University of Zurich, Zurich, Switzerland.
⁴ Department of Biology, ETHZ, Zurich, Switzerland.
⁵ Human Genetics, Faculty of Medicine and Health Sciences, University of Oldenburg, Germany.
⁶ Research Center Neurosensory Science, University Oldenburg, Germany.
⁷ Sagol School of Neuroscience, Tel Aviv University, Tel Aviv, Israel.

Abstract

Splicing of transcripts is catalyzed by the spliceosome, a mega-complex consisting of hundreds of proteins and five snRNAs, which employs direct interactions. When U1 snRNA forms high-affinity binding, namely more than eight base pairs, with the 5'SS, the result is usually a suppressing effect on the splicing activity. This likely occurs due to the inefficient unwinding of U1/5'SS base-pairing or other regulatory obstructions. Here, we show in vitro and in patient-derived cell lines that pre-microRNAs can modulate the splicing reaction by interacting with U1 snRNA. This leads to reduced binding affinity to the 5'SS, and hence promotes the inclusion of exons containing 5'SS, despite sequence-based high affinity to U1. Application of the mechanism resulted in correction of the splicing defect in the disease-causing VCAN gene from an individual with Wagner syndrome. This pre-miRNA/U1 interaction can regulate the expression of alternatively spliced exons, thus extending the scope of mechanisms regulating splicing.

Keywords: Cell biology; Functional aspects of cell biology; Molecular biology.