用新方法从单细胞大模型中提取通用调控知识,提升基因网络推断效果
Towards Universal Gene Regulatory Network Inference: Unlocking Generalizable Regulatory Knowledge in Single-cell Foundation Models
- 设计零样本基准测试,评估模型对未知基因和数据集的泛化能力
- 提出两种新方法,从大模型中挖掘隐含调控信号,生成通用基因特征
- 显著超越现有方法,适合研究基因调控与单细胞数据建模的学者
基因调控网络(GRN)推断对于理解复杂细胞机制至关重要,单细胞转录组数据使其成为可能。随着单细胞基础模型(scFMs)的出现,转录组编码能力的提升被普遍认为将革新GRN推断。然而我们发现其性能仍不理想,主要原因是标准重构预训练目标难以显式捕捉潜在调控信号。为此,我们首先构建了一个评估未见基因和数据集上调控预测能力的通用性基准,依赖scFMs的零样本能力,传统方法难以应对。为进一步释放基础模型中的调控知识,我们提出两种新方法:虚拟值扰动与梯度轨迹,可将scFMs中的隐含调控信息提炼为高度通用的基因间特征。大量实验表明,本方法显著优于现有方法,建立了一种利用scFMs实现通用GRN推断的新范式。
原文摘要 · Abstract (English)
Gene Regulatory Network (GRN) inference is essential for understanding complex cellular mechanisms, rendered tractable through single-cell transcriptomic data. With the emergence of single-cell Foundation Models (scFMs), enhanced transcriptomic encoding is widely expected to revolutionize GRN inference. However, we observe that their performance remains far from satisfactory. The primary reason is that the standard reconstruction-based pre-training objectives often fail to explicitly capture latent regulatory signals. To bridge this gap, we first introduce a GRN generalization benchmark designed to evaluate regulatory predictions on unseen genes and datasets, which relies on the zero-shot capabilities of scFMs and is inherently challenging for traditional methods. Furthermore, to unlock the regulatory knowledge within the foundation models, we propose two novel methods, Virtual Value Perturbation and Gradient Trajectory, to distill implicit regulatory information from scFMs into highly generalizable inter-gene features. Extensive experiments demonstrate that our approach significantly outperforms existing methods, establishing a new paradigm for leveraging the potential of scFMs in universal GRN inference.
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