GT-GRN: a graph transformer framework for enhanced gene regulatory network inference via multimodal embedding of expression data and existing network knowledge.

Abstract

The inference of gene regulatory networks (GRNs) is critical for understanding the regulatory mechanisms underlying cellular development, functional specialization, and disease progression. Predicting regulatory gene interactions-often framed as a link prediction task-is a foundational step toward modeling cellular behavior. However, GRN inference from gene coexpression data alone is limited by noise, low interpretability, and difficulty in capturing indirect regulatory signals. Additionally, challenges such as data sparsity, nonlinearity, and complex gene interactions hinder accurate network reconstruction. To address these issues, we propose, a novel graph transformer (GT) based framework (GT-GRN) that enhances GRN inference by integrating multimodal gene embeddings. Our method combines three complementary sources of information: (i) autoencoder-based embeddings, which capture high-dimensional gene expression patterns while preserving biological signals; (ii) structural embeddings, derived from previously inferred GRNs and encoded via random walks and a Bidirectional Encoder Representations from Transformers (BERT) based language model to learn global gene representations; (iii) positional encodings, capturing each gene's role within the network topology . These heterogeneous features are fused and processed using a GT, allowing the joint modeling of both local and global regulatory structures. Experimental results on benchmark datasets show that GT-GRN outperforms existing GRN inference methods in predictive accuracy and robustness. Furthermore, it reconstructs cell-type-specific GRNs with high fidelity and produces gene embeddings that generalize to other tasks such as cell-type annotation.