arXiv:2503.01682cs.LG2025-03ACL被引 2

将基因调控网络融入RNA基础模型,提升药物反应预测精度。

GRNFormer: A Biologically-Guided Framework for Integrating Gene Regulatory Networks into RNA Foundation Models

  • 构建分层基因调控网络,融合多组学数据
  • 通过图注意力与边扰动策略提升模型性能
  • 适合生物信息学与精准医疗研究者使用

单细胞RNA测序的基础模型在捕捉基因表达模式方面展现潜力,但现有方法忽视了基因调控关系中的生物学先验知识,且未能充分利用可提供互补调控信息的多组学信号。本文提出GRNFormer框架,系统性地将多尺度基因调控网络(GRNs)整合进RNA基础模型训练中。该框架引入两项关键创新:一是构建分层级的GRNs,捕获细胞类型特异及细胞特异的调控关系;二是设计结构感知集成框架,通过两项技术改进解决GRNs中的信息不对称问题:(1) 使用多头交叉注意力的图拓扑适配器动态加权调控关系;(2) 提出新型边扰动策略,以生物学合理的共表达连接扰动GRNs,增强图神经网络训练。在多个模型架构上针对三个典型下游任务进行综合实验,结果表明GRNFormer显著优于当前最先进基线:药物反应预测相关性提升3.6%,单细胞药物分类AUC提高9.6%,基因扰动预测准确率平均提升1.1%。

原文摘要 · Abstract (English)

Foundation models for single-cell RNA sequencing (scRNA-seq) have shown promising capabilities in capturing gene expression patterns. However, current approaches face critical limitations: they ignore biological prior knowledge encoded in gene regulatory relationships and fail to leverage multi-omics signals that could provide complementary regulatory insights. In this paper, we propose GRNFormer, a new framework that systematically integrates multi-scale Gene Regulatory Networks (GRNs) inferred from multi-omics data into RNA foundation model training. Our framework introduces two key innovations. First, we introduce a pipeline for constructing hierarchical GRNs that capture regulatory relationships at both cell-type-specific and cell-specific resolutions. Second, we design a structure-aware integration framework that addresses the information asymmetry in GRNs through two technical advances: (1) A graph topological adapter using multi-head cross-attention to weight regulatory relationships dynamically, and (2) a novel edge perturbation strategy that perturb GRNs with biologically-informed co-expression links to augment graph neural network training. Comprehensive experiments have been conducted on three representative downstream tasks across multiple model architectures to demonstrate the effectiveness of GRNFormer. It achieves consistent improvements over state-of-the-art (SoTA) baselines: $3.6\%$ increase in drug response prediction correlation, $9.6\%$ improvement in single-cell drug classification AUC, and $1.1\%$ average gain in gene perturbation prediction accuracy.

基因调控基础模型多组学图神经网络

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