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RNA-coupled CRISPR Screens Reveal ZNF207 as a Regulator of LMNA Aberrant Splicing in Progeria [siZNF207_Rescue_mRNA-Seq]

GSE284630 Homo sapiens Expression profiling by high throughput sequencing 8 samples Submitted 2025/09/16 Platform GPL34284
Summary
Despite progress in understanding pre-mRNA splicing, the regulatory mechanisms controlling most alternative splicing events remain unclear. We developed CRASP-Seq, a method that integrates pooled CRISPR-based genetic perturbations with deep sequencing of splicing reporters, to quantitively assess the impact of all human genes on alternative splicing from a single RNA sample. CRASP-Seq identified both known and novel regulators, enriched for proteins involved in RNA splicing and metabolism. As proof-of-concept, CRASP-Seq analysis of an LMNA cryptic splicing event linked to progeria uncovered ZNF207, primarily known for mitotic spindle assembly, as a regulator of progerin splicing. ZNF207 depletion enhances canonical LMNA splicing and decreases progerin levels in patient-derived cells. We further show that ZNF207’s zinc finger domain broadly impacts alternative splicing through direct interactions with U1 snRNP components. These findings position ZNF207 as a U1 snRNP auxiliary factor and demonstrate the power of CRASP-Seq to uncover key regulators and domains of alternative splicing.
Published in
RNA-coupled CRISPR screens reveal ZNF207 as a regulator of LMNA aberrant splicing in progeria
Behera AK, Kim JJ, Kordale S et al. · Molecular cell 2026 · PMID 41475346 · doi:10.1016/j.molcel.2025.12.003
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Also filed as BioProject PRJNA1199966 and SRA study SRP552548. Searching any of these in the dataset finder brings you back here.

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