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.
Highlights
More than half of the human genome consists of transposable elements (TEs)
This work provides a foundation to design strategies to control Human Silencing Hub (HUSH) activity, with important potential therapeutic applications. Both N- and C-terminal regions of Periphilin are required for HUSH function To identify the subdomains of Periphilin required for HUSH function, we generated various Periphilin constructs with N- or C-terminal truncations and assessed their silencing activity as part of the HUSH complex (Fig. 1A)
The loss of HUSH function with the 350∆374 and 1∆127 Periphilin mutants could be due to loss of an intrinsic activity of Periphilin or failure of Periphilin to be recruited to the HUSH complex
Summary
More than half of the human genome consists of transposable elements (TEs). TEs have evolved to fulfill important cellular functions. TEs drive the evolution of transcriptional networks by spreading transcription factor binding sites, promoters and other regulatory elements (Chuong et al, 2016; Friedli & Trono, 2015). TE-derived regulatory elements are important in embryogenesis, when global hypomethylation promotes transcription. Key pluripotencyassociated transcription factors involved in cell fate determination bind to sites within TEs (Friedli & Trono, 2015). TE genes serve as a genetic reservoir that can be coopted by the host. TE-derived proteins catalyze V(D)J recombination (Zhou et al, 2004) and syncytiotrophoblast fusion in placental development (Dupressoir et al, 2012; Friedli & Trono, 2015)
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
