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bioRxiv · 10.1101/2023.09.20.555752

Discovering chromatin dysregulation induced by protein-coding perturbations at scale

Frenkel, M.·Hujoel, M. L. A.·Morris, Z.·Raman, S.
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Abstract

Although population-scale databases have expanded to millions of protein-coding variants, insight into variant mechanisms has not kept pace. We present PROD-ATAC, a high-throughput method for discovering the effects of protein-coding variants on chromatin. A pooled library of variants is expressed in a disease-agnostic cell line, and single-cell ATAC resolves each variants effect on chromatin. Using PROD-ATAC, we characterized the effects of >100 oncofusions (a class of cancer-causing chimeric proteins) and controls and revealed that pioneer activity is a common feature of fusions spanning an enormous range of fusion frequencies. Further, 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 pioneering is common among oncofusions. This work provides a global view of fusion-induced chromatin. We uncovered convergent mechanisms among disparate oncofusions and shared modes of dysregulation across different cancers. PROD-ATAC is generalizable to any set of protein-coding variants.

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Frenkel, M., Hujoel, M. L. A., Morris, Z., Raman, S.. 2023-09-21. Discovering chromatin dysregulation induced by protein-coding perturbations at scale. https://doi.org/10.1101/2023.09.20.555752

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