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

The Human Silencing Hub (HuSH) complex is a complex that silences retrotransposable elements invertebrates. Here, we identify a second HuSH complex, designated HuSH2, which is centered aroundTASOR2, a paralog of the core TASOR protein in HuSH. Our findings reveal that HuSH and HuSH2 localize todistinct and non-overlapping genomic loci. Specifically, HuSH localizes to and represses LINE-1retrotransposons, whereas HuSH2 targets and represses KRAB-ZNFs and interferon signaling and responsegenes. We use in silico protein structure predictions to simulate MPP8 interactions with TASOR paralogs,guiding amino acid substitutions that disrupted binding to HuSH complexes. These MPP8 transgenes andother constructs reveal the importance of HuSH complex quantities in regulating LINE-1 activity. Furthermore,our results suggest that dynamic changes in TASOR and TASOR2 expression enable cells to finely tuneHuSH-mediated silencing. This study offers insights into the interplay of HuSH complexes, highlighting theirvital role in retrotransposon regulation.