GenPerturb: sequence-grounded interpretation of perturbation transcriptomes using pretrained genomic models

Abstract

BackgroundPerturb-seq captures transcriptional responses to thousands of genetic and chemical perturbations, but does not directly resolve the cis-regulatory elements or transcription factor motifs underlying those responses. Existing approaches rely on indirect post hoc analyses or external epigenomic annotations, making it difficult to connect gene-level responses to specific regulatory element ResultsWe present GenPerturb, a framework that leverages pretrained sequence-to-expression models to link perturbation-induced expression changes to candidate cis-regulatory elements. By contrasting perturbation and control states, GenPerturb prioritizes regulatory regions and transcription factor motifs associated with each perturbation. The model recapitulates perturbation-dependent gene expression patterns and enables sequence-level interpretation without requiring matched chromatin data. Across multiple perturbation types, GenPerturb identifies biologically meaningful regulatory programs, including lineage-specific and signaling-associated motif activities, even when corresponding transcription factor expression changes are limited. ConclusionsGenPerturb converts gene-level expression responses from Perturb-seq into perturbation-specific, sequence-grounded cis-regulatory hypotheses. By prioritizing candidate regulatory elements and transcription factor motifs responsive to each perturbation without requiring matched chromatin data, GenPerturb enables mechanistic interpretation of transcriptional regulation and guides downstream experimental validation.