More than half of the human genome consists of transposons, DNA sequences that can ‘jump’ around within the genome. Left unchecked these elements can cause genomic instability – a hallmark of cancer – but the elements also play important roles in human development.
Christopher Douse, a new researcher at Lund Stem Cell Center, spent the past five years at Cambridge University characterizing a newly-identified protein complex – known as HUSH, the Human Silencing Hub – which regulates these mobile genetic elements and integrating retroviruses. The clinical importance of HUSH has recently been highlighted – not only has the complex been identified as an HIV restriction factor, but numerous reports identify that patients with mutations in MORC2, a key component of the complex, exhibit severe neurodevelopmental disorders.
In one study published last week in Nature Communications, Christopher and colleagues dissect the biochemical assembly of the HUSH complex and its activity against a class of transposons called LINE-1. The second paper, published at the end of September in Nucleic Acids Research, reports how one of the HUSH components promotes aggregation of the complex at target loci. Together, they have identified a feedback loop initiated by HUSH, in which epigenetic regulatory enzymes are recruited in response to transcription, repressing the bound transposon and modifying the surrounding chromatin.
“HUSH and its effector enzyme MORC2 are clearly important for the suppression of transposable elements and regulation of genome stability.” explains Christopher. “However, despite the recent clinical reports on patient MORC2 mutations, and early embryonic lethality of mouse knockouts, very little is known about the complex’s role during development”
Whilst at Lund Stem Cell Center, Christopher will build on his work from Cambridge, focusing on the importance of MORC2 during neural development and on understanding the how this complex interplays with other chromatin regulation pathways.
Researcher Christopher Douse is supported by the ‘Stora Anslag’ from SSMF (Svenska Sällskapet för Medicinska Forskning) and by Crafoordska stiftelsen. He is currently working within the Molecular Neurogenetics research group, led by Prof. Johan Jakobsson.
Links to articles:
https://www.nature.com/articles/s41467-020-18761-6
https://academic.oup.com/nar/advance-article/doi/10.1093/nar/gkaa785/5911750
https://www.nature.com/articles/s41467-018-03045-x