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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.

Motivation Self-supervised pre-training models for molecular data have demonstrated notable results across many downstream tasks. The inherent multimodal properties of molecules have also motivated efforts to capture information from different modalities. However, current multimodal molecular pre-training models usually treat these modalities as equal and independent, despite differences in their information content. Three-dimensional (3D) molecular structures generally contain finer-grained information than the simplified molecular-input line-entry system (SMILES), which primarily captures higher-level semantic information, such as molecular topology.

Results We designed a cross-modal mask-predict pre-training model, CrossMol, to capture semantic associations between modalities with unequal information volumes. The model completes missing 3D structure using higher-level semantic information from another modality, such as SMILES. This allows it to learn cross-modal associations and better understand fine-grained 3D structural information. We also introduce a reweighted distance prediction loss to improve the modelling of short-range structural information. Experiments show that CrossMol achieves large performance gains on multiple downstream molecular tasks, attaining state-of-the-art results.

Availability and implementation The source code and training data are available at https://github.com/zhengkangjie/crossmol. The code is archived at https://doi.org/10.5281/zenodo.19653204.

Protein language models have demonstrated significant potential in the field of protein engineering. However, current protein language models primarily operate at the residue scale, which limits their ability to provide information at the atom level. This limitation prevents us from fully exploiting the capabilities of protein language models for applications involving both proteins and small molecules. In this paper, we propose ESM-AA (ESM All-Atom), a novel approach that enables atom-scale and residue-scale unified molecular modeling. ESM-AA achieves this by pre-training on multi-scale code-switch protein sequences and utilizing a multi-scale position encoding to capture relationships among residues and atoms. Experimental results indicate that ESM-AA surpasses previous methods in protein-molecule tasks, demonstrating the full utilization of protein language models. Further investigations reveal that through unified molecular modeling, ESM-AA not only gains molecular knowledge but also retains its understanding of proteins.

SMILES, a crucial textual representation of molecular structures, has garnered significant attention as a foundation for pre-trained language models (LMs). However, most existing pre-trained SMILES LMs focus solely on the single-token level supervision during pre-training, failing to fully leverage the substructural information of molecules. This limitation makes the pre-training task overly simplistic, preventing the models from capturing richer molecular semantic information. Moreover, during pre-training, these SMILES LMs only process corrupted SMILES inputs, never encountering any valid SMILES, which leads to a train-inference mismatch. To address these challenges, we propose SMI-Editor, a novel edit-based pre-trained SMILES LM. SMI-Editor disrupts substructures within a molecule at random and feeds the resulting SMILES back into the model, which then attempts to restore the original SMILES through an editing process. This approach not only introduces fragment-level training signals, but also enables the use of valid SMILES as inputs, allowing the model to learn how to reconstruct complete molecules from these incomplete structures. As a result, the model demonstrates improved scalability and an enhanced ability to capture fragment-level molecular information. Experimental results show that SMI-Editor achieves state-of-the-art performance across multiple downstream molecular tasks, and even outperforming several 3D molecular representation models.

3D molecular representation learning has gained tremendous interest and achieved promising performance in various downstream tasks. A series of recent approaches follow a prevalent framework: an encoder-only model coupled with a coordinate denoising objective. However, through a series of analytical experiments, we prove that the encoder-only model with coordinate denoising objective exhibits inconsistency between pre-training and downstream objectives, as well as issues with disrupted atomic identifiers. To address these two issues, we propose Mol-AE for molecular representation learning, an auto-encoder model using positional encoding as atomic identifiers. We also propose a new training objective named 3D Cloze Test to make the model learn better atom spatial relationships from real molecular substructures. Empirical results demonstrate that Mol-AE achieves a large margin performance gain compared to the current state-of-the-art 3D molecular modeling approach.

Masked Language Models (MLMs) have achieved remarkable success in many self-supervised representation learning tasks. MLMs are trained by randomly masking portions of the input sequences with [MASK] tokens and learning to reconstruct the original content based on the remaining context. This paper explores the impact of [MASK] tokens on MLMs.

Analytical studies show that masking tokens can introduce the corrupted semantics problem, wherein the corrupted context may convey multiple, ambiguous meanings. This problem is also a key factor affecting the performance of MLMs on downstream tasks. Based on these findings, we propose a novel enhanced-context MLM, ExLM. Our approach expands [MASK] tokens in the input context and models the dependencies between these expanded states.

This enhancement increases context capacity and enables the model to capture richer semantic information, effectively mitigating the corrupted semantics problem during pre-training. Experimental results demonstrate that ExLM achieves significant performance improvements in both text modeling and SMILES modeling tasks. Further analysis confirms that ExLM enriches semantic representations through context enhancement, and effectively reduces the semantic multimodality commonly observed in MLMs.

Levenshtein Transformer (LevT) is a widely-used text-editing model, which generates a sequence based on editing operations (deletion and insertion) in a non-autoregressive manner. However, it is challenging to train the key refinement components of LevT due to training-inference discrepancy. By carefully designing experiments, our work reveals that the deletion module is under-trained while the insertion module is over-trained due to the imbalance training signals for the two refinement modules. Based on these observations, we further propose a dual learning approach that can remedy the imbalance training by feeding an initial input to both refinement modules, which is consistent with the process in inference. Experimental results on three representative NLP tasks demonstrate the effectiveness and universality of the proposed approach.

Length-control summarization aims to condense long texts into a short one within a certain length limit. Previous approaches often use autoregressive (AR) models and treat the length requirement as a soft constraint, which may not always be satisfied. In this study, we propose a novel length-control decoding algorithm based on the Directed Acyclic Transformer (DAT). Our approach allows for multiple plausible sequence fragments and predicts a path to connect them. In addition, we propose a Sequence Maximum a Posteriori (SeqMAP) decoding algorithm that marginalizes different possible paths and finds the most probable summary satisfying the length budget. Our algorithm is based on beam search, which further facilitates a reranker for performance improvement. Experimental results on the Gigaword and DUC2004 datasets demonstrate our state-of-the-art performance for length-control summarization.

While non-autoregressive sign language translation (NASLT) has the advantage in inference speed, the translation quality of NASLT models lags significantly behind that of the state-of-the-art (SOTA) autoregressive sign language translation (ASLT) models. To bridge the quality gap, we exploit glosses to unlock the potential of NASLT models. Concretely, we propose Gloss-enhanced Levenshtein Transformer (GLevT) for sign language translation (SLT), which takes glosses as initial sequences for editing into texts. In particular, to alleviate the inconsistency between training and inference of GLevT, which is introduced by glosses, we propose a dual-centric learning policy and a keyframe-based gloss replacement method for training, further improving the translation quality of GLevT. Experiments on CSL-Daily demonstrate that GLevT outperforms other NASLT models by approximately 4 points in BLEU and ROUGE scores, while achieving performance comparable to the SOTA ASLT models with a 3.46~5.26× inference speed-up. Furthermore, we extend GLevT to gloss-free SLT, achieving performance comparable to SOTA large models, despite having only 49M parameters. We release code at https://github.com/XMUDeepLIT/GLevT.