Predicting dynamic expression patterns in budding yeast with a fungal DNA language model.

Abstract

Predicting gene expression from DNA sequence remains challenging due to complex regulatory codes. We introduce a masked DNA language model pretrained on 165 fungal genomes closely related to budding yeast that captures conserved regulatory grammar. Fine-tuning the LM on yeast RNA-seq data-including high-resolution transcriptional regulator induction time courses generated in this study-yielded Shorkie, a model that substantially improves gene expression prediction compared to baselines trained without self-supervision. Shorkie identified canonical transcription factor (TF) binding motifs and tracked their usage across induction experiments. Furthermore, Shorkie accurately predicted variant effects, outperforming leading sequence-to-expression models in cis-eQTL classification and achieving high concordance with massively parallel reporter assays. Interpretability analyses revealed Shorkie's ability to resolve promoter dynamics, splicing signals, and temporal changes in regulatory motif usage. This framework demonstrates that evolutionary-scale pretraining combined with transfer learning substantially improves our ability to decode gene regulation from sequence, providing insights into noncoding variants and regulatory networks.