Inverted Alu repeats: friends or foes in the human transcriptome

Alu elements are highly abundant primate-specific short interspersed nuclear elements that account for ~10% of the human genome. Due to their preferential location in gene-rich regions, especially in introns and 3' UTRs, Alu elements can exert regulatory effects on the expression of both host and neighboring genes. When two Alu elements with inverse orientations are positioned in close proximity, their transcription results in the generation of distinct double-stranded RNAs (dsRNAs), known as inverted Alu repeats (IRAlus). IRAlus are key immunogenic self-dsRNAs and post-transcriptional cis-regulatory elements that play a role in circular RNA biogenesis, as well as RNA transport and stability. Recently, IRAlus dsRNAs have emerged as regulators of transcription and activators of Z-DNA-binding proteins. The formation and activity of IRAlus can be modulated through RNA editing and interactions with RNA-binding proteins, and misregulation of IRAlus has been implicated in several immune-associated disorders. In this review, we summarize the emerging functions of IRAlus dsRNAs, the regulatory mechanisms governing IRAlus activity, and their relevance in the pathogenesis of human diseases.