Research by Marta Seczynska, led by Paul Lehner (both Medicine, CITIID) in collaboration with Sergio Martinez Cuesta (Discovery Sciences, AstraZeneca) shows how the HUSH complex protects the human genome from foreign (retroelement) invasion.
The human genome is under constant threat from invasion by mobile genetic elements. These include viruses (such as HIV) and retrotransposons (Line 1) which make up 17% of our genome. The Lehner group previously described theHuman Silencing Hub (HUSH) complex and showed how it silences genome invaders through chromatin (H3K9me3) modification. How HUSH recognizes these invading genetic elements was unknown.
Published in Nature, the researchers show how HUSH has the remarkable ability to distinguish ‘self’ from ‘non-self’ genomic DNA through the recognition of ‘intronless’ cDNA, the hallmark of reverse transcription. In mammalian genes DNA coding regions (exons) comprise small islands within a vast sea of non-coding DNA (introns). Retroelements, being RNA-derived, lack classical non-coding introns, so intronless cDNA allows HUSH to discriminate invaders from host genes, and thus regulate the reverse flow of genetic information (from RNA to DNA).
HUSH therefore provides a genome immuno-surveillance system which silences invading DNAs and has important therapeutic implications: HUSH is an epigenetic checkpoint that suppresses tumour-intrinsic immunogenicity and is a novel immunotherapeutic target for cancer therapies. Since HUSH silences diverse DNA sequences, including long cDNAs of human genes, HUSH inhibition will improve gene expression (gene therapy).