Discovering chromatin dysregulation induced by protein-coding perturbations at scale

Max Frenkel; Margaux L A Hujoel; Zachary Morris; Srivatsan Raman

doi:10.1101/2023.09.20.555752

Discovering chromatin dysregulation induced by protein-coding perturbations at scale

bioRxiv [Preprint]. 2023 Sep 21:2023.09.20.555752. doi: 10.1101/2023.09.20.555752.

Authors

Max Frenkel^{1

2

3}, Margaux L A Hujoel^{4

5

6}, Zachary Morris⁷, Srivatsan Raman^{3

8

9}

Affiliations

¹ Cellular and Molecular Biology Graduate Program, University of Wisconsin, Madison, Wisconsin, USA.
² Medical Scientist Training Program, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin, USA.
³ Department of Biochemistry, University of Wisconsin, Madison, Wisconsin, 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, Wisconsin, USA.
⁸ Department of Bacteriology, University of Wisconsin, Madison, Wisconsin, USA.
⁹ Department of Chemical and Biological Engineering, University of Wisconsin, Madison, Wisconsin, USA.

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 variant's 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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