Strategies for effectively modelling promoter-driven gene expression using transfer learning

The ability to deliver genetic cargo to human cells is enabling rapid progress in molecular medicine, but designing this cargo for precise expression in specific cell types is a major challenge. Expression is driven by regulatory DNA sequences within short synthetic promoters, but relatively few of these promoters are cell-type-specific. The ability to design cell-type-specific promoters using model-based optimization would be impactful for research and therapeutic applications. However, models of expression from short synthetic promoters (promoter-driven expression) are lacking for most cell types due to insufficient training data in those cell types. Although there are many large datasets of both endogenous expression and promoter-driven expression in other cell types, which provide information that could be used for transfer learning, transfer strategies remain largely unexplored for predicting promoter-driven expression. Here, we propose a variety of pretraining tasks, transfer strategies, and model architectures for modelling promoter-driven expression. To thoroughly evaluate various methods, we propose two benchmarks that reflect data-constrained and large dataset settings. In the data-constrained setting, we find that pretraining followed by transfer learning is highly effective, improving performance by 24-27%. In the large dataset setting, transfer learning leads to more modest gains, improving performance by up to 2%. We also propose the best architecture to model promoter-driven expression when training from scratch. The methods we identify are broadly applicable for modelling promoter-driven expression in understudied cell types, and our findings will guide the choice of models that are best suited to designing promoters for gene delivery applications using model-based optimization. Our code and data are available at https://github.com/anikethjr/promoter_models.