Large-scale discovery of chromatin dysregulation induced by oncofusions and other protein-coding variants

  • Nat Biotechnol. 2024 Jul 24. doi: 10.1038/s41587-024-02347-4.
Max Frenkel  1  2  3 ,  James E Corban  3 ,  Margaux L A Hujoel  4  5  6 ,  Zachary Morris  7 ,  Srivatsan Raman  8  9  10
Affiliations
  • 1. Cellular and Molecular Biology Graduate Program, University of Wisconsin-Madison, Madison, WI, USA.
  • 2. Medical Scientist Training Program, University of Wisconsin School of Medicine and Public Health, Madison, WI, USA.
  • 3. Department of Biochemistry, University of Wisconsin-Madison, Madison, WI, USA.
  • 4. Division of Genetics, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA.
  • 5. Center for Data Sciences, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA.
  • 6. Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
  • 7. Department of Human Oncology, University of Wisconsin School of Medicine and Public Health, Madison, WI, USA.
  • 8. Department of Biochemistry, University of Wisconsin-Madison, Madison, WI, USA. [email protected].
  • 9. Department of Bacteriology, University of Wisconsin-Madison, Madison, WI, USA. [email protected].
  • 10. Department of Chemical and Biological Engineering, University of Wisconsin-Madison, Madison, WI, USA. [email protected].
PMID: 39048711 DOI: 10.1038/s41587-024-02347-4
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.

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