Abstract
The HUSH complex represses retroviruses, transposons and genes to maintain the integrity of vertebrate genomes. HUSH regulates deposition of the epigenetic mark H3K9me3, but how its three core subunits — TASOR, MPP8 and Periphilin — contribute to assembly and targeting of the complex remains unknown. Here, we define the biochemical basis of HUSH assembly and find that its modular architecture resembles the yeast RNA-induced transcriptional silencing complex. TASOR, the central HUSH subunit, associates with RNA processing components. TASOR is required for H3K9me3 deposition over LINE-1 repeats and repetitive exons in transcribed genes. In the context of previous studies, this suggests that an RNA intermediate is important for HUSH activity. We dissect the TASOR and MPP8 domains necessary for transgene repression. Structure-function analyses reveal TASOR bears a catalytically-inactive PARP domain necessary for targeted H3K9me3 deposition. We conclude that TASOR is a multifunctional pseudo-PARP that directs HUSH assembly and epigenetic regulation of repetitive genomic targets.
Highlights
The human silencing hub (HUSH) complex represses retroviruses, transposons and genes to maintain the integrity of vertebrate genomes
Transcription promotes target binding by the HUSH subunit M-phase phosphoprotein 8 (MPP8), and HUSH loci were found in transcriptionally-active euchromatic regions as defined by epigenetic marks[15,16] and sensitivity to sonication[4]
This study provides a molecular characterization of transgene activation suppressor (TASOR) and how it contributes to HUSH function
Summary
The HUSH complex represses retroviruses, transposons and genes to maintain the integrity of vertebrate genomes. HUSH regulates deposition of the epigenetic mark H3K9me[3], but how its three core subunits — TASOR, MPP8 and Periphilin — contribute to assembly and targeting of the complex remains unknown. Genetic experiments studying position-effect variegation (PEV) in model organisms have identified much of the machinery involved in the formation of H3K9me[3] domains[7]. Such position effects refer to the influence of local chromatin environment on gene expression. HUSH is a complex of three proteins: transgene activation suppressor (TASOR), M-phase phosphoprotein 8 (MPP8), and Periphilin (PPHLN1, isoform 2). While these data suggest that MPP8 binding to methylated ATF7IP recruits SETDB1 to spread H3K9me[3] over HUSH targets[23], a read-write mechanism for H3K9me[3] spreading involving MPP8 and ATF7IP/
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