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Enhancer–promoter interaction (EPI) is a critical component of gene regulation. Accurately predicting EPIs across diverse cell types can advance our understanding of the molecular mechanisms behind transcriptional regulation and provide valuable insights into the onset and progression of related diseases. At present, large-scale genome-wide EPI predictions typically rely on computational approaches. However, most of these methods focus on predicting EPIs within a single cell line and lack a global perspective encompassing multiple cell lines. Furthermore, they often fail to fully account for the nonlinear relationships between features, leading to suboptimal prediction accuracy. In this study, we propose KansformerEPI, a global EPI prediction model designed for multiple cell lines. The model is built on Kansformer, an encoder that integrates KAN and Transformer, effectively capturing the nonlinear relationships among various epigenetic and sequence features. We utilized KansformerEPI to achieve cross-tissue prediction of EPIs across different cell types. This approach enhances the model’s scalability, eliminating the complexity of designing separate prediction models for individual tissues. As a result, our model is applicable to various tissues, thereby reducing dependency on extensive datasets. Experimental results demonstrate that KansformerEPI surpasses existing methods such as TransEPI, TargetFinder, and SPEID in both accuracy and stability of EPI predictions across datasets including HMEC, IMR90, K562, and NHEK.

KansformerEPI: a deep learning framework integrating KAN and transformer for predicting enhancer–promoter interactions