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Periphilin self-association underpins epigenetic silencing by the HUSH complex

Prigozhin, Daniil M ; Douse, Christopher H LU orcid ; Albecka, Anna ; Tchasovnikarova, Iva A ; Timms, Richard T ; Oda, Shun-Ichiro ; Adolf, Frank ; Freund, Stefan M V ; Maslen, Sarah and Lehner, Paul J , et al. (2020) In Nucleic Acids Research 48(18). p.10313-10328
Abstract

Transcription of integrated DNA from viruses or transposable elements is tightly regulated to prevent pathogenesis. The Human Silencing Hub (HUSH), composed of Periphilin, TASOR and MPP8, silences transcriptionally active viral and endogenous transgenes. HUSH recruits effectors that alter the epigenetic landscape and chromatin structure, but how HUSH recognizes target loci and represses their expression remains unclear. We identify the physicochemical properties of Periphilin necessary for HUSH assembly and silencing. A disordered N-terminal domain (NTD) and structured C-terminal domain are essential for silencing. A crystal structure of the Periphilin-TASOR minimal core complex shows Periphilin forms an α-helical homodimer, bound by a... (More)

Transcription of integrated DNA from viruses or transposable elements is tightly regulated to prevent pathogenesis. The Human Silencing Hub (HUSH), composed of Periphilin, TASOR and MPP8, silences transcriptionally active viral and endogenous transgenes. HUSH recruits effectors that alter the epigenetic landscape and chromatin structure, but how HUSH recognizes target loci and represses their expression remains unclear. We identify the physicochemical properties of Periphilin necessary for HUSH assembly and silencing. A disordered N-terminal domain (NTD) and structured C-terminal domain are essential for silencing. A crystal structure of the Periphilin-TASOR minimal core complex shows Periphilin forms an α-helical homodimer, bound by a single TASOR molecule. The NTD forms insoluble aggregates through an arginine/tyrosine-rich sequence reminiscent of low-complexity regions from self-associating RNA-binding proteins. Residues required for TASOR binding and aggregation were required for HUSH-dependent silencing and genome-wide deposition of repressive mark H3K9me3. The NTD was functionally complemented by low-complexity regions from certain RNA-binding proteins and proteins that form condensates or fibrils. Our work suggests the associative properties of Periphilin promote HUSH aggregation at target loci.

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publication status
published
subject
keywords
Antigens, Neoplasm/chemistry, Crystallography, X-Ray, DNA Transposable Elements/genetics, Epigenesis, Genetic/genetics, Gene Silencing, Humans, Nuclear Proteins/chemistry, Phosphoproteins/chemistry, Protein Aggregates/genetics, Protein Binding/genetics, Protein Conformation, alpha-Helical, Protein Domains/genetics, RNA-Binding Proteins/chemistry, Transcription, Genetic, Viruses/genetics
in
Nucleic Acids Research
volume
48
issue
18
pages
10313 - 10328
publisher
Oxford University Press
external identifiers
  • scopus:85092750410
  • pmid:32976585
ISSN
1362-4962
DOI
10.1093/nar/gkaa785
language
English
LU publication?
yes
additional info
© The Author(s) 2020. Published by Oxford University Press on behalf of Nucleic Acids Research.
id
69c307fe-439d-4d4e-abcc-9282537b6f2e
date added to LUP
2022-06-14 21:00:12
date last changed
2025-01-10 11:06:28
@article{69c307fe-439d-4d4e-abcc-9282537b6f2e,
  abstract     = {{<p>Transcription of integrated DNA from viruses or transposable elements is tightly regulated to prevent pathogenesis. The Human Silencing Hub (HUSH), composed of Periphilin, TASOR and MPP8, silences transcriptionally active viral and endogenous transgenes. HUSH recruits effectors that alter the epigenetic landscape and chromatin structure, but how HUSH recognizes target loci and represses their expression remains unclear. We identify the physicochemical properties of Periphilin necessary for HUSH assembly and silencing. A disordered N-terminal domain (NTD) and structured C-terminal domain are essential for silencing. A crystal structure of the Periphilin-TASOR minimal core complex shows Periphilin forms an α-helical homodimer, bound by a single TASOR molecule. The NTD forms insoluble aggregates through an arginine/tyrosine-rich sequence reminiscent of low-complexity regions from self-associating RNA-binding proteins. Residues required for TASOR binding and aggregation were required for HUSH-dependent silencing and genome-wide deposition of repressive mark H3K9me3. The NTD was functionally complemented by low-complexity regions from certain RNA-binding proteins and proteins that form condensates or fibrils. Our work suggests the associative properties of Periphilin promote HUSH aggregation at target loci.</p>}},
  author       = {{Prigozhin, Daniil M and Douse, Christopher H and Albecka, Anna and Tchasovnikarova, Iva A and Timms, Richard T and Oda, Shun-Ichiro and Adolf, Frank and Freund, Stefan M V and Maslen, Sarah and Lehner, Paul J and Modis, Yorgo}},
  issn         = {{1362-4962}},
  keywords     = {{Antigens, Neoplasm/chemistry; Crystallography, X-Ray; DNA Transposable Elements/genetics; Epigenesis, Genetic/genetics; Gene Silencing; Humans; Nuclear Proteins/chemistry; Phosphoproteins/chemistry; Protein Aggregates/genetics; Protein Binding/genetics; Protein Conformation, alpha-Helical; Protein Domains/genetics; RNA-Binding Proteins/chemistry; Transcription, Genetic; Viruses/genetics}},
  language     = {{eng}},
  month        = {{10}},
  number       = {{18}},
  pages        = {{10313--10328}},
  publisher    = {{Oxford University Press}},
  series       = {{Nucleic Acids Research}},
  title        = {{Periphilin self-association underpins epigenetic silencing by the HUSH complex}},
  url          = {{http://dx.doi.org/10.1093/nar/gkaa785}},
  doi          = {{10.1093/nar/gkaa785}},
  volume       = {{48}},
  year         = {{2020}},
}