A mechanism-informed deep neural network enables prioritization of regulators that drive cell state transitions

Xi Xi, Jiaqi Li, Jinmeng Jia, Qiuchen Meng, Chen Li, Xiaowo Wang, Lei Wei and Xuegong Zhang ()
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Xi Xi: Tsinghua University
Jiaqi Li: Tsinghua University
Jinmeng Jia: Tsinghua University
Qiuchen Meng: Tsinghua University
Chen Li: Tsinghua University
Xiaowo Wang: Tsinghua University
Lei Wei: Tsinghua University
Xuegong Zhang: Tsinghua University

Nature Communications, 2025, vol. 16, issue 1, 1-18

Abstract: Abstract Cells are regulated at multiple levels, from regulations of individual genes to interactions across multiple genes. Some recent neural network models can connect molecular changes to cellular phenotypes, but their design lacks modeling of regulatory mechanisms, limiting the decoding of regulations behind key cellular events, such as cell state transitions. Here, we present regX, a deep neural network incorporating both gene-level regulation and gene-gene interaction mechanisms, which enables prioritizing potential driver regulators of cell state transitions and providing mechanistic interpretations. Applied to single-cell multi-omics data on type 2 diabetes and hair follicle development, regX reliably prioritizes key transcription factors and candidate cis-regulatory elements that drive cell state transitions. Some regulators reveal potential new therapeutic targets, drug repurposing possibilities, and putative causal single nucleotide polymorphisms. This method to analyze single-cell multi-omics data demonstrates how the interpretable design of neural networks can better decode biological systems.

Date: 2025
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DOI: 10.1038/s41467-025-56475-9

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