Specific inhibition of splicing factor activity by decoy RNA oligonucleotides

Polina Denichenko, Maxim Mogilevsky, Antoine Cléry, Thomas Welte, Jakob Biran, Odelia Shimshon, Georgina D. Barnabas, Miri Danan-Gotthold, Saran Kumar, Eylon Yavin, Erez Y. Levanon, Frédéric H. Allain, Tamar Geiger, Gil Levkowitz and Rotem Karni ()
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Polina Denichenko: Hebrew University-Hadassah Medical School
Maxim Mogilevsky: Hebrew University-Hadassah Medical School
Antoine Cléry: ETH Zurich
Thomas Welte: GmbH
Jakob Biran: Weizmann Institute of Science
Odelia Shimshon: Hebrew University-Hadassah Medical School
Georgina D. Barnabas: Tel Aviv University
Miri Danan-Gotthold: Bar-Ilan University
Saran Kumar: Hebrew University-Hadassah Medical School
Eylon Yavin: Hebrew University-Hadassah Medical School
Erez Y. Levanon: Bar-Ilan University
Frédéric H. Allain: ETH Zurich
Tamar Geiger: Tel Aviv University
Gil Levkowitz: Weizmann Institute of Science
Rotem Karni: Hebrew University-Hadassah Medical School

Nature Communications, 2019, vol. 10, issue 1, 1-15

Abstract: Abstract Alternative splicing, a fundamental step in gene expression, is deregulated in many diseases. Splicing factors (SFs), which regulate this process, are up- or down regulated or mutated in several diseases including cancer. To date, there are no inhibitors that directly inhibit the activity of SFs. We designed decoy oligonucleotides, composed of several repeats of a RNA motif, which is recognized by a single SF. Here we show that decoy oligonucleotides targeting splicing factors RBFOX1/2, SRSF1 and PTBP1, can specifically bind to their respective SFs and inhibit their splicing and biological activities both in vitro and in vivo. These decoy oligonucleotides present an approach to specifically downregulate SF activity in conditions where SFs are either up-regulated or hyperactive.

Date: 2019
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DOI: 10.1038/s41467-019-09523-0

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