Periphilin self-association underpins epigenetic silencing by the HUSH complex.
Accepted version
Peer-reviewed
Repository URI
Repository DOI
Change log
Authors
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 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.
Description
Keywords
Journal Title
Conference Name
Journal ISSN
1362-4962
Volume Title
Publisher
Publisher DOI
Rights
Sponsorship
Wellcome Trust (201387/Z/16/Z)
Wellcome Trust (101908/Z/13/Z)
Biotechnology and Biological Sciences Research Council (BB/N011791/1)
Wellcome Trust (210688/Z/18/Z)
MRC (MR/V011561/1)
Wellcome Trust (217191/Z/19/Z)