ArticleProceedings of the National Academy of Sciences of the United States of America2024
The HUSH epigenetic repressor complex silences PML nuclear body-associated HSV-1 quiescent genomes.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2024. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 8 papers.
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Who cites it
8 citing papers in PubMed.
- HSV-1 metabolic hijacking: Mechanisms to precision therapeutics.Virulence · 2026Review
- Epigenetic regulation of transgenes.Journal of biotechnology · 2026Review
- From infection to dysfunction: viral triggers and antiviral immune factors in Alzheimer's disease pathology.Frontiers in immunology · 2026Review
- Interferon dependent immune memory during HSV-1 neuronal latency via increased H3K9me3 and restriction by ATRX.Nature communications · 2025Article
- The HUSH complex facilitates the exit of pluripotency.Communications biology · 2025Article
- Chromatin Regulation of HSV Gene Transcription.Viruses · 2025Review
- Structure and Function of PML Nuclear Bodies: A Brief Overview of Key Cellular Roles.Biomolecules · 2025Review
- Identification and characterization of a human MORC2 DNA binding region that is required for gene silencing.Nucleic acids research · 2025Article
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Authors and funding
18 authors.
Funding
Abstract
Herpes simplex virus 1 (HSV-1) latently infected neurons display diverse patterns in the distribution of the viral genomes within the nucleus. A key pattern involves quiescent HSV-1 genomes sequestered in promyelocytic leukemia nuclear bodies (PML NBs) forming viral DNA-containing PML-NBs (vDCP NBs). Using a cellular model that replicates vDCP NB formation, we previously demonstrated that these viral genomes are chromatinized with the H3.3 histone variant modified on its lysine 9 by trimethylation (H3.3K9me3), a mark associated with transcriptional repression. Here, we identify the HUSH complex and its effectors, SETDB1 and MORC2, as crucial for the acquisition of H3K9me3 on PML NB-associated HSV-1 and the maintenance of HSV-1 transcriptional repression. ChIP-seq analyses show H3K9me3 association with the entire viral genome. Inactivating the HUSH-SETDB1-MORC2 complex before infection significantly reduces H3K9me3 on the viral genome, with minimal impact on the cellular genome, aside from expected changes in LINE-1 retroelements. Depletion of HUSH, SETDB1, or MORC2 alleviates HSV-1 repression in infected primary human fibroblasts and human induced pluripotent stem cell-derived sensory neurons (hiPSDN). We found that the viral protein ICP0 induces MORC2 degradation via the proteasome machinery. This process is concurrent with ICP0 and MORC2 depletion capability to reactivate silenced HSV-1 in hiPSDN. Overall, our findings underscore the robust antiviral function of the HUSH-SETDB1-MORC2 repressor complex against a herpesvirus by modulating chromatin marks linked to repression, thus presenting promising avenues for anti-herpesvirus therapeutic strategies.
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