scooby: modeling multimodal genomic profiles from DNA sequence at single-cell resolution

Understanding how regulatory sequences shape gene expression across individual cells is a fundamental challenge in genomics. Joint RNA sequencing and epigenomic profiling provides opportunities to build models capturing sequence determinants across steps of gene expression. However, current models, developed primarily for bulk omics data, fail to capture the cellular heterogeneity and dynamic processes revealed by single-cell multimodal technologies. Here, we introduce scooby, a framework to model genomic profiles of single-cell RNA-sequencing coverage and single-cell assay for transposase-accessible chromatin using sequencing insertions from sequence at single-cell resolution. For this, we leverage the pretrained multiomics profile predictor Borzoi and equip it with a cell-specific decoder. Scooby recapitulates cell-specific expression levels of held-out genes and identifies regulators and their putative target genes. Moreover, scooby allows resolving single-cell effects of bulk expression quantitative trait loci and delineating their impact on chromatin accessibility and gene expression. We anticipate scooby to aid unraveling the complexities of gene regulation at the resolution of individual cells.