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Retrotransposition — the reverse flow of genetic information from RNA to DNA is the major route by which new genetic material enters our genome, with retroelements comprising over 40% of human DNA. This process drives innovation but threatens genome integrity, demanding precise regulation. Our discovery of the Human Silencing Hub (HUSH) revealed a genome-wide transcriptional immunosurveillance system that detects and epigenetically silences invading DNA. How HUSH distinguishes self from invading DNA was unclear. We found that HUSH discriminates ‘self’ from ‘non-self’ based on introns: The majority of cellular genes are intron-containing, while RNA-derived retroelements are intronless, marking their cDNA as foreign. This intron-based recognition mechanism uncovers an unexpected innate immune surveillance system that protects the genome from the reverse flow of genetic information.
