Genome-wide CRISPR screenings identified SMCHD1 as a host-restricting factor for AAV transduction.

PLoS Pathog

Center of Growth Metabolism and Aging, State Key Laboratory of Oral Disease, West China Hospital of Stomatology, Key Laboratory of Bio-Resource and Eco-Environment of Ministry of Education, Animal Disease Prevention and Food Safety Key Laboratory of Sichuan Province, College of Life Sciences, Sichuan University, Chengdu, China.

Published: July 2024

AI Article Synopsis

  • AAV gene therapy often requires high viral doses, which can lead to immune responses and patient safety concerns due to limited understanding of how the host interacts with the virus post-transduction.
  • A genome-wide CRISPR screen identified SMCHD1 as a key factor that inhibits AAV transgene expression by repressing transcription and maintaining a heterochromatin-like state.
  • Disrupting the SMCHD1 protein complex through techniques like RNAi or CRISPR leads to increased AAV transcription, suggesting that targeting host factors involved in chromatin remodeling could enhance AAV-based gene therapy.

Article Abstract

AAV-mediated gene therapy typically requires a high dose of viral transduction, risking acute immune responses and patient safety, part of which is due to limited understanding of the host-viral interactions, especially post-transduction viral genome processing. Here, through a genome-wide CRISPR screen, we identified SMCHD1 (Structural Maintenance of Chromosomes Hinge Domain 1), an epigenetic modifier, as a critical broad-spectrum restricting host factor for post-entry AAV transgene expression. SMCHD1 knock-down by RNAi and CRISPRi or knock-out by CRISPR all resulted in significantly enhanced transgene expression across multiple viral serotypes, as well as for both single-strand and self-complementary AAV genome types. Mechanistically, upon viral transduction, SMCHD1 effectively repressed AAV transcription by the formation of an LRIF1-HP1-containing protein complex and directly binding with the AAV genome to maintain a heterochromatin-like state. SMCHD1-KO or LRIF1-KD could disrupt such a complex and thus result in AAV transcriptional activation. Together, our results highlight the host factor-induced chromatin remodeling as a critical inhibitory mechanism for AAV transduction and may shed light on further improvement in AAV-based gene therapy.

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Source
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC11257396PMC
http://dx.doi.org/10.1371/journal.ppat.1012344DOI Listing

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