Silencing the Past – Enabling the Future: HUSH-Mediated Regulation of Retroelements

Abstract

Retrotransposition — the reverse flow of genetic information from RNA to DNA provides 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 effective 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 cellular 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. Our ongoing work on HUSH-mediated epigenetic repression will be further discussed.