CoChat
Sign Up
Cited by 22Chromosomal and Genetic VariationsGenomics and Chromatin DynamicsEpigenetics and DNA Methylation

The DOI matches its Crossref record; 3 of the 3 references it cites were found in a registry or an index.

Interplay between Two Paralogous Human Silencing Hub (HuSH) Complexes in Regulating LINE-1 Element Silencing

Open access
Jensvold, Zena D., Flood, Julia R., Christenson, Anna E., Lewis, Peter W.·2024·Nature Communications
DOI 10.1038/s41467-024-53761-wPMC PMC11532391

Published version of a preprint

Open this paper in CoChat — free accountOpen PDF

Abstract

Abstract The Human Silencing Hub (HuSH) complex is composed of TASOR, MPP8, and PPHLN1 subunits and serves as a conserved protein complex responsible for silencing transposable elements in vertebrate animals. Despite its importance, the regulatory mechanisms and recruitment dynamics governing this complex remain poorly understood. In this study, we have identified a second HuSH complex, termed HuSH2, centered around TASOR2, a paralog of the core TASOR protein in HuSH. Our findings indicate that every subunit in both HuSH and HuSH2 has an important role in achieving precise genomic localization to distinct, non-overlapping genomic loci. We utilized in silico protein structure prediction to simulate the interactions between MPP8 and both TASOR paralogs. Drawing on the insights gained from these predictions, we implemented amino acid substitutions that interfered with the binding of MPP8 to each HuSH complex. Leveraging these MPP8 transgenes and other constructs, we identified an important role played by the relative quantities of HuSH complexes in controlling the activity of LINE-1 elements. Furthermore, our results suggest that dynamic changes in TASOR and TASOR2 expression enable cells to finely tune the extent of HuSH-mediated silencing. Our study provides insights into the intricate interplay between HuSH complexes, illuminating their important role in the regulation of retrotransposon silencing. Key Points The identification of a previously unknown HuSH2 complex, with TASOR2 as its central component. HuSH and HuSH2 complexes exhibit unique genomic localization patterns within the human genome. Disruption of the delicate balance between the two HuSH complexes results in the desilencing of LINE-1. TASOR and TASOR2 engage in a competitive interaction for the HuSH subunit MPP8. The localization of MPP8 to either HuSH or HuSH2 sites is intricately regulated by its interaction with TASOR and TASOR2.

Overview

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

Integrity signals

Registry

Crossref · 10.1038/s41467-024-53761-w

Cites

3 of 3 references verified0 citation errors · 0 not checkable

Statistics

Verification

Claims the paper makes

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

The self-check needs the paper’s full text.

Citations

Cites

Flagged first, then by citations

Research works printed but not linked: 36

  1. Tchasovnikarova, I. A. et al. Epigenetic silencing by the HUSH complex mediates position-effect variegation in human cells. Science 348, 1481–1485 (2015). · DOI
  2. Tchasovnikarova, I. A. et al. Hyperactivation of HUSH complex function by Charcot–Marie–Tooth disease mutation in MORC2. Nat. Genet. 49, 1035–1044 (2017). · DOI
  3. Timms, R. T., Tchasovnikarova, I. A., Antrobus, R., Dougan, G. & Lehner, P. J. ATF7IP-mediated stabilization of the histone methyltransferase SETDB1 is essential for heterochromatin formation by the HUSH complex. Cell Rep. 17, 653–659 (2016). · DOI
  4. Liu, N. et al. Selective silencing of euchromatic L1s revealed by genome-wide screens for L1 regulators. Nature 553, 228–232 (2018). · DOI
  5. Seczynska, M., Bloor, S., Cuesta, S. M. & Lehner, P. J. Genome surveillance by HUSH-mediated silencing of intronless mobile elements. Nature 601, 440–445 (2021). · DOI
  6. Douse, C. H. et al. TASOR is a pseudo-PARP that directs HUSH complex assembly and epigenetic transposon control. Nat. Commun. 11, 1–16 (2020). · DOI
  7. Robbez-Masson, L. et al. The HUSH complex cooperates with TRIM28 to repress young retrotransposons and new genes. Genome Res. 28, 836–845 (2018). · DOI · Paper page
  8. Spencley, A. L. et al. Co-transcriptional genome surveillance by HUSH is coupled to termination machinery. Mol. Cell 83, 1623–1639.e8 (2023). · DOI
  9. Zhu, Y., Wang, G. Z., Cingöz, O. & Goff, S. P. NP220 mediates silencing of unintegrated retroviral DNA. Nature 564, 278–282 (2018). · DOI · Paper page
  10. Tsusaka, T. et al. Tri-methylation of ATF7IP by G9a/GLP recruits the chromodomain protein MPP8. Epigenet. Chromatin 11, 56 (2018). · DOI
  11. Marnef, A. et al. A cohesin/HUSH-and LINC-dependent pathway controls ribosomal DNA double-strand break repair. Genes Dev. 33, 1–16 (2019). · DOI
  12. Müller, I. et al. MPP8 is essential for sustaining self-renewal of ground-state pluripotent stem cells. Nat. Commun. 12, 3034 (2021). · DOI
  13. Prigozhin, D. M. et al. Periphilin self-association underpins epigenetic silencing by the HUSH complex. Nucleic Acids Res. 48, 10313–10328 (2020). · DOI
  14. Schöpp, T. et al. The DUF3715 domain has a conserved role in RNA-directed transposon silencing. RNA https://doi.org/10.1261/RNA.079693.123 (2023). · DOI
  15. Li, S., Wang, L., Berman, M., Kong, Y.-Y. & Dorf, M. E. Mapping a dynamic innate immunity protein interaction network regulating type I interferon production. Immunity 35, 426–440 (2011). · DOI
  16. Hubel, P. et al. A protein-interaction network of interferon-stimulated genes extends the innate immune system landscape. Nat. Immunol. 20, 493–502 (2019). · DOI
  17. Schoggins, J. W. & Rice, C. M. Interferon-stimulated genes and their antiviral effector functions. Curr. Opin. Virol. 1, 519–525 (2011). · DOI
  18. Jensvold, Z. D., Christenson, A. E., Flood, J. R. & Lewis, P. W. Interplay between Two Paralogous Human Silencing Hub (HuSH) Complexes in Regulating LINE-1 Element Silencing. bioRxiv https://doi.org/10.1101/2023.12.28.573526 (2023). · DOI
  19. Danac, J. M. C. et al. Competition between two HUSH complexes orchestrates the immune response to retroelement invasion. Mol. Cell 84, 2870–2881.e5 (2024). · DOI
  20. Matkovic, R. et al. TASOR epigenetic repressor cooperates with a CNOT1 RNA degradation pathway to repress HIV. RNA 29, 1471–1480 (2023). · DOI
  21. Chougui, G. et al. HIV-2/SIV viral protein X counteracts HUSH repressor complex. Nat. Microbiol. 3, 891–897 (2018). · DOI
  22. Machida, S. et al. Exploring histone loading on HIV DNA reveals a dynamic nucleosome positioning between unintegrated and integrated viral genome. Proc. Natl Acad. Sci. USA https://doi.org/10.1073/pnas.1913754117 (2020). · DOI
  23. Yurkovetskiy, L. et al. Primate immunodeficiency virus proteins Vpx and Vpr counteract transcriptional repression of proviruses by the HUSH complex. Nat. Microbiol. 3, 1354–1361 (2018). · DOI
  24. Cuellar, T. L. et al. Silencing of retrotransposons by SETDB1 inhibits the interferon response in acute myeloid leukemia. J. Cell Biol. 216, 3535–3549 (2017). · DOI
  25. Gu, Z. et al. Silencing of LINE-1 retrotransposons is a selective dependency of myeloid leukemia. Nat. Genet. 53, 672–682 (2021). · DOI
  26. Zhang, Y., Wen, Z., Washburn, M. P. & Florens, L. Refinements to label free proteome quantitation: How to deal with peptides shared by multiple proteins. Anal. Chem. 82, 2272–2281 (2010). · DOI
  27. Wickham, H. Ggplot2: Elegant Graphics for Data Analysis (Springer-Verlag New York, 2016). · DOI
  28. Perez-Riverol, Y. et al. The PRIDE database resources in 2022: a hub for mass spectrometry-based proteomics evidences. Nucleic Acids Res. 50, D543–D552 (2022). · DOI · Paper page
  29. Danecek, P. et al. Twelve years of SAMtools and BCFtools. Gigascience 10, 1–4 (2021). · DOI
  30. Ramírez, F. et al. deepTools2: a next generation web server for deep-sequencing data analysis. Nucleic Acids Res. 44, W160–W165 (2016). · DOI · Paper page
  31. Zhang, Y. et al. Model-based analysis of ChIP-Seq (MACS). Genome Biol. 9, 1–9 (2008). · DOI · Paper page
  32. Heinz, S., Benner, C., Spann, N. & Bertolino, E. Simple combinations of lineage-determining transcription factors prime cis-regulatory elements required for macrophage and B cell identities. Mol. Cell 38, 576–589 (2010). · DOI · Paper page
  33. Robinson, J. T. et al. Integrative genomics viewer. Nat. Biotechnol. 29, 24 (2011). · DOI · Paper page
  34. Dobin, A. et al. STAR: ultrafast universal RNA-seq aligner. Bioinformatics 29, 15–21 (2013). · DOI · Paper page
  35. Patro, R., Duggal, G., Love, M. I., Irizarry, R. A. & Kingsford, C. Salmon provides fast and bias-aware quantification of transcript expression. Nat. Methods 14, 417–419 (2017). · DOI · Paper page
  36. Robinson, M. D., McCarthy, D. J. & Smyth, G. K. edgeR: a Bioconductor package for differential expression analysis of digital gene expression data. Bioinformatics 26, 139–140 (2010). · DOI · Paper page

Metadata

Authors
Jensvold, Z. D., Flood, J. R., Christenson, A. E., & Lewis, P. W.
Affiliations
University of Wisconsin–Madison (US)
Corresponding author
Lewis, Peter W.
ORCID
Venue
Nature Communications
Publisher
Springer Science and Business Media LLC
Published
2024-11-03
Volume
15
Issue
1
Pages
9492-9492
ISSN
2041-1723 (ISSN-L)
DOI
10.1038/s41467-024-53761-w
PMC
PMC11532391
OpenAlex
W4404008828
Cited by
22
References
3
Citations by year
2026: 9 · 2025: 8 · 2024: 5
FWCI
5.37
Type
journal article
Language
en
Open access
Licence
Locations
  • Nature Communications (publishedVersion, cc-by-nc-nd)
  • bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by-nc-nd)
  • Research Square (acceptedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by-nc-nd)
  • PubMed (publishedVersion)
  • PubMed Central (submittedVersion, cc-by-nc-nd)
  • RePEc: Research Papers in Economics (submittedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders
U.S. Department of Health & Human Services | National Institutes of Health (P01CA196539)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Chromosomal and Genetic Variations
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics and Chromatin Dynamics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Epigenetics and DNA Methylation
Keywords
LINE-1 retrotransposons, retrotransposon silencing, paralogs, MPP8, KRAB zinc finger proteins, protein-protein interaction, protein structure prediction, genomic localization, transposon regulation

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

Are you an author, or do you see a problem with this page? Request a review