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Large-scale discovery of chromatin dysregulation induced by oncofusions and other protein-coding variants.
- Source :
-
Nature biotechnology [Nat Biotechnol] 2024 Jul 24. Date of Electronic Publication: 2024 Jul 24. - Publication Year :
- 2024
- Publisher :
- Ahead of Print
-
Abstract
- Population-scale databases have expanded to millions of protein-coding variants, yet insight into their mechanistic consequences has lagged. Here we present PROD-ATAC, a high-throughput method for discovering the effects of protein-coding variants on chromatin regulation. A pooled variant library is expressed in a disease-agnostic cell line, and single-cell assay for transposase-accessible chromatin resolves each variant's effect on the chromatin landscape. Using PROD-ATAC, we characterized the effects of more than 100 oncofusions (cancer-causing chimeric proteins) and controls and revealed that chromatin remodeling is common to fusions spanning an enormous range of fusion frequencies. Furthermore, fusion-induced dysregulation can be context agnostic, as observed mechanisms often overlapped with cancer and cell-type-specific prior knowledge. We also showed that gain-of-function activity is common among oncofusions. This work begins to outline a global map of fusion-induced chromatin alterations. We suggest that there might be convergent mechanisms among disparate oncofusions and shared modes of dysregulation among fusions present in tumors at different frequencies. PROD-ATAC is generalizable to any set of protein-coding variants.<br /> (© 2024. The Author(s), under exclusive licence to Springer Nature America, Inc.)
Details
- Language :
- English
- ISSN :
- 1546-1696
- Database :
- MEDLINE
- Journal :
- Nature biotechnology
- Publication Type :
- Academic Journal
- Accession number :
- 39048711
- Full Text :
- https://doi.org/10.1038/s41587-024-02347-4