Cells must distinguish their own transcripts from those of genomic parasites, including transposable elements. Small RNA pathways solve this problem through base pairing, using sequence complementarity to identify transcripts for silencing. Mammalian cells also possess a second strategy that operates without a guide RNA. The HUSH complex is thought to preferentially engage nascent transcripts through their intrinsic properties rather than their sequence, preferentially engaging long and poorly spliced nascent RNAs over the spliced messages that dominate the host transcriptome, and converting this recognition into H3K9me3-marked heterochromatin. In this view, splicing may serve as a marker of self, whereas its absence can mark an RNA as a candidate for silencing. LINE-1 retrotransposons, which produce long intronless transcripts, represent a major physiological substrate of this pathway.
Our laboratory investigates how HUSH functions as a flexible RNA surveillance system in different developmental and physiological contexts. I will discuss our recent work on the physiological roles of HUSH-mediated transposon silencing, and how these studies are beginning to reveal the principles by which mammalian cells distinguish genomic parasites from their own transcripts.