MUSS: A Multi-scale and Sequence-based Model for Single-cell Gene Regulation

Abstract

Modeling gene regulation in single cells requires jointly representing DNA sequence, chromatin accessibility, and gene expression across regulatory scales. Sequence-based models capture DNA-level regulatory grammar but often lack cell-level resolution, whereas many single-cell omics models represent genes and peaks as fixed-vocabulary tokens without their underlying sequence. Here, we present MUSS, a sequence-based multi-scale model for single-cell gene regulation that preserves both DNA-level and cell-level resolution. MUSS derives peak- and gene-level representations from DNA using a frozen pre-trained sequence encoder and integrates them through peak-peak self-attention and distance-biased peak-gene interactions. Peak masked language modeling followed by training on paired scATAC-seq and scRNA-seq aligns these representations with cell-specific regulatory states. Across gene expression prediction, enhancer-gene linking, motif-guided regulatory prioritization, and zero-shot cell clustering, MUSS achieves strong performance against sequence-based and single-cell omics baselines. It further predicts expression for genes and peaks unseen during task training. These results support sequence-grounded, multi-scale representations for decoding cell-type-specific regulatory programs. Code, datasets, and model checkpoints are available at https://github.com/Lotfollahi-lab/MUSS_neurips26.