Discovering chromatin dysregulation induced by protein-coding perturbations at scale.
Max FrenkelMargaux L A HujoelZachary S MorrisSrivatsan RamanPublished in: bioRxiv : the preprint server for biology (2023)
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.
Keyphrases
- single cell
- gene expression
- copy number
- high throughput
- dna damage
- transcription factor
- genome wide
- protein protein
- papillary thyroid
- high glucose
- amino acid
- machine learning
- diabetic rats
- clinical trial
- randomized controlled trial
- squamous cell carcinoma
- oxidative stress
- cell therapy
- endothelial cells
- big data
- mesenchymal stem cells
- lymph node metastasis