Refining sequence-to-activity models by increasing model resolution

Abstract Decoding the cis-regulatory syntax that controls gene expression is essential for improving our understanding of cell differentiation and disease. Deep learning based sequence-to-activity (S2A) models learn to identify regulatory motifs and their syntax through modeling chromatin accessibility. Previously, we developed AI-TAC, a S2A model that predicts chromatin accessibility across various immune cell types in multi-task fashion, effectively decoding the regulatory syntax underlying immune cell differentiation. While ATAC-seq is commonly used to measure regional accessibility, it also provides high-resolution profiles, the distribution of Tn5 insertion sites, that offer additional insights into the precise location and strength of TF binding sites. Here we present bpAI-TAC, a base-pair resolution ATAC-seq model, and demonstrate that modeling ATAC-seq profiles alongside accessibility consistently improves predictions of differential chromatin accessibility across cell types. Moreover, we find that multi-task learning across related immune cell types consistently outperforms single-task models. To understand what additional information bpAI-TAC learns from ATAC-seq profiles, we systematically compare sequence attributions from models trained with and without ATAC-seq profiles. We identify novel motifs with strong effect sizes that emerge when profile data is included. Our findings suggest that modeling ATAC-seq at base-pair resolution enables the model to learn a more nuanced and sensitive representation of the cis-regulatory syntax driving immune cell-specific chromatin landscapes.