Molecular mechanisms of retroelement control by the Human Silencing Hub

Summary

The Human Silencing Hub (HUSH) guards the genome from the pathogenic effects of retroelement expression. Composed of MPP8, TASOR, and Periphilin-1, HUSH recognizes actively transcribed retrotransposed sequences by the presence of long (>1.5-kb) nascent transcripts without introns.

HUSH recruits MORC2, a chromatin remodeler, and other effectors that degrade transcripts or deposit transcriptionally repressive marks. HUSH and MORC2 are essential for life and point mutations in MORC2 can cause severe neuropathies including Charcot Marie Tooth disease and spinal muscular atrophy.

Project aims

This PhD project will address how HUSH recognizes active retroelements and how MORC2 contributes to transcriptional repression. Molecular structures of MORC2 in complex with HUSH components will be determined. The biological activities of MORC2-HUSH complexes will be assessed, including nucleosome remodeling activity.

We will also explore the molecular properties of the C-terminal half of MORC2, which is required for HUSH repression, and of a TASOR orthologue, TASOR2, which was recently shown to regulate the expression of interferon-stimulated genes.

We will apply a complementary set of biochemical and structural approaches including cryo-EM, X-ray crystallography, biochemical assay and cell-based assays. Our work may contribute to the development of therapeutics for neuropathies or for immuno-oncology applications.

The Modis group is committed to fostering an inclusive, diverse, and supportive research environment.

References

1. Nikolopoulos et al (2024) DOI: 10.1101/2023.12.21.572340
2. Danac et al (2024) DOI: 10.1016/j.molcel.2024.06.020
3. Douse et al (2020) DOI: 10.1038/s41467-020-18761-6
4. Prigozhin et al (2020) DOI: 10.1093/nar/gkaa785

Contact details

Professor Yorgo Modis - ym10000@cam.ac.uk

Opportunities

This project is open to applicants who want to do a:

• PhD