Deep learning linking mechanistic models to single-cell transcriptomics data reveals transcriptional bursting in response to DNA damage.

Cells must adopt flexible regulatory strategies to make decisions regarding their fate, including differentiation, apoptosis, or survival in the face of various external stimuli. One key cellular strategy that enables these functions is stochastic gene expression programs. However, understanding how transcriptional bursting, and consequently, cell fate, responds to DNA damage on a genome-wide scale poses a challenge. In this study, we propose an interpretable and scalable inference framework, DeepTX, that leverages deep learning methods to connect mechanistic models and single-cell RNA sequencing (scRNA-seq) data, thereby revealing genome-wide transcriptional burst kinetics. This framework enables rapid and accurate solutions to transcription models and the inference of transcriptional burst kinetics from scRNA-seq data. Applying this framework to several scRNA-seq datasets of DNA-damaging drug treatments, we observed that fluctuations in transcriptional bursting induced by different drugs were associated with distinct fate decisions: 5'-iodo-2'-deoxyuridine treatment was associated with differentiation in mouse embryonic stem cells by increasing the burst size of gene expression, while low- and high-dose 5-fluorouracil treatments in human colon cancer cells were associated with changes in burst frequency that corresponded to apoptosis- and survival-related fate, respectively. Together, these results show that DeepTX enables genome-wide inference of transcriptional bursting from single-cell transcriptomics data and can generate hypotheses about how bursting dynamics relate to cell fate decisions.