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Novel CRISPR activation sgRNA libraries identify tumour essential genes, therapy resistance genes, and cancer oncogenes

ABSTRACT: CRISPR activation (CRISPRa) enables precise upregulation of gene expression for ex vivo and in vivo applications. However, a lack of scalable, high-coverage tools has limited comprehensive genetic screening in murine models. Here, we introduce Partita, a next-generation mouse whole-genome CRISPRa sgRNA platform, designed for unparalleled efficiency in gene activation studies. Partita employs a high-density targeting strategy, deploying 10 sgRNAs per transcriptional start site, structured into five gene class-specific sub-libraries to maximise transcriptional induction. To demonstrate the capabilities of Partita, we performed a series of large-scale screens: an in vitro enrichment/depletion screen, whole-genome CRISPRa screens in a double-hit lymphoma model to uncover resistance factors to pro-apoptotic drugs (venetoclax, nutlin-3a, etoposide), and an in vivo screen to identify accelerators of MYC-driven lymphomagenesis. Each experiment revealed both expected and novel regulators, with high validation rates. By enabling robust gain-of-function screening, Partita unlocks new avenues for functional genomics and expands the toolkit for discovering key drivers of biological processes across diverse research fields.

ORGANISM(S): Mus musculus

PROVIDER: GSE296642 | GEO | 2026/08/31

REPOSITORIES: GEO

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