Abstract

The Human Silencing Hub (HuSH) complex silences retrotransposable elements in vertebrates. Here, we identify a second HuSH complex, designated HuSH2, which is centered around TASOR2, a paralog of the core TASOR protein in HuSH. Our findings reveal that HuSH and HuSH2 localize to distinct and non-overlapping genomic loci. Specifically, HuSH localizes to and represses LINE-1 retrotransposons, whereas HuSH2 targets and represses KRAB-ZNFs and interferon signaling and response genes. 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 and other 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 tune HuSH-mediated silencing. This study offers insights into the interplay of HuSH complexes, highlighting their vital role in retrotransposon regulation.

The study identifies HuSH2, a paralogous complex to HuSH, centered around TASOR2, and distinct in its genomic localization and function. HuSH represses LINE-1 retrotransposons, while HuSH2 regulates interferon signaling genes.

Details

Title
Interplay between Two Paralogous Human Silencing Hub (HuSH) Complexes in Regulating LINE-1 Element Silencing
Author
Jensvold, Zena D. 1   VIAFID ORCID Logo  ; Flood, Julia R. 1 ; Christenson, Anna E. 1   VIAFID ORCID Logo  ; Lewis, Peter W. 1   VIAFID ORCID Logo 

 University of Wisconsin, Department of Biomolecular Chemistry, School of Medicine and Public Health, Madison, USA (GRID:grid.14003.36) (ISNI:0000 0001 2167 3675) 
Pages
9492
Publication year
2024
Publication date
2024
Publisher
Nature Publishing Group
e-ISSN
20411723
Source type
Scholarly Journal
Language of publication
English
ProQuest document ID
3123593442
Copyright
© The Author(s) 2024. This work is published under http://creativecommons.org/licenses/by-nc-nd/4.0/ (the “License”). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.