Alu-mediated RNA duplexes are associated with widespread exon skipping across primate transcriptomes

TL;DR

This paper shows that RNA structures formed by Alu repeats are linked to exon skipping in primates and are regulated by specific RNA-binding proteins.

Contribution

The study reveals that Alu-mediated RNA duplexes are a major driver of exon skipping divergence in primate transcriptomes.

Findings

Most long-range intronic RNA duplexes are mediated by inverted Alu-repeat elements.

Alu-derived RNA duplexes are associated with divergent exon skipping patterns in primates.

RNA binding proteins HNRNPC, ILF2, and ILF3 regulate Alu duplex-associated splicing.

Abstract

Alternative splicing patterns have diverged rapidly during vertebrate evolution. By integrating genome-wide predictions of stable RNA duplexes, alternative splicing profiles, and proximity ligation-detection of RNA-RNA interactions, we observe that the majority of long-range intronic RNA duplexes are mediated by inverted Alu-repeat elements, and that these structures are associated with divergent exon skipping patterns in primates. We further observe evidence that the RNA binding proteins HNRNPC, ILF2 and ILF3 directly control Alu duplex-associated alternative splicing levels. Collectively, our results provide evidence that Alu-derived RNA duplexes modulated by RNA binding proteins have contributed to the remarkable divergence in alternative splicing patterns during mammalian evolution.

The online version contains supplementary material available at 10.1186/s13059-026-04029-7.

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