How HUSH protects the genome from reverse genetic flow

All life forms defend their genome against nucleic acid invasion, yet RNA-derived retroelements make up >40% of our DNA. Retrotransposition, the predominant route by which our genome acquires new genetic material, is therefore tolerated but must be tightly regulated. We discovered the HUSH epigenetic repressor complex and characterized its central role in genome defence through repression of RNA-derived retroelements (retroviruses/retrotransposons). How HUSH distinguishes retroelements from endogenous genes was unclear. We showed how cellular introns provide a novel means for self-nonself discrimination, with HUSH specifically silencing intronless (RNA-derived) transgenes. HUSH therefore regulates the reverse flow of genetic information (RNA-DNA) in the genome, providing a means of post-integration immunity. Here we will elucidate the signals which trigger HUSH recruitment and chromatin-dependent silencing. In particular, the molecular features of intronless genes that recruit HUSH, how introns protect against HUSH and how transcription initiates HUSH-dependent silencing. We will determine how RNA-mediated (canonical) HUSH silencing differs from DNA-mediated (non-canonical) HUSH-dependent silencing and ascertain the importance of HUSH-dependent repression in specialised cells, including hiPSC and the germline. Understanding the different modes of recruitment, and how specialised intronless genes and viruses evolved to evade HUSH-mediated silencing, will provide an integrated understanding of HUSH's role in genome defence.