Gene regulatory networks govern cell fate transitions through dynamic causal mechanisms. Since exhaustively mapping this vast perturbation space experimentally is prohibitive, scalable computational models are essential. Yet, current frameworks fall short because they infer statistical co-expression rather than physical mechanisms, remain blind to non-canonical regulators lacking classical DNA-binding motifs, and fail to generalize across unseen perturbation factors or cell lines. Here we show that a multimodal biophysical framework, VitaGRN, overcomes these barriers by constructing a biophysical regulatory scaffold from multimodal evidence and propagating interactions to capture non-canonical regulators. By leveraging structurally aligned protein embeddings, VitaGRN predicts zero-shot perturbation responses and uncovers non-canonical translational control programs. Notably, VitaGRN demonstrates robust generalization across unseen factors, cell lines, and developmental transitions. Ultimately, VitaGRN generates a con[fi]dence-calibrated virtual perturbation atlas spanning over a thousand factors. This resource reframes gene regulatory networks from static correlation graphs into dynamically generalizable and mechanistically transparent models, streamlining wet-lab candidate prioritization.
Yang, Z., Huang, S., Bai, G., Dong, J., Wang, J., Li, S. Z.
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