构建可扩展的基因网络模型,解析单细胞中基因调控的动态变化。
A scalable gene network model of regulatory dynamics in single cells
- 基于基因网络结构的微分方程模型,融合调控关系建模动态响应。
- 在髓系分化与K562扰动测序数据中准确推断基因敲除的转录机制。
- 适用于大规模单细胞时序数据,支持小分子扰动下的轨迹模拟。
单细胞数据提供了细胞转录状态的高维测量,但从中提取基因调控功能的洞察,特别是识别生物扰动影响的转录机制,仍具挑战性。许多扰动会引发细胞代偿反应,难以区分基因调控的直接与间接效应。建模基因调控如何塑造这些响应的时序动态,是理解生物扰动的关键。基于微分方程的动力学模型能系统刻画转录动态,但其在单细胞数据中的应用受限于计算成本、随机性、稀疏性和噪声。现有方法要么依赖低维表示,要么做强简化假设,难以规模化建模转录动态。我们提出一种功能可学习的细胞动力学模型FLeCS,将基因网络结构嵌入耦合微分方程,以建模基因调控功能。给定(伪)时间序列单细胞数据,FLeCS能高效推断大规模细胞动态,在髓系分化和K562 Perturb-seq实验中揭示基因敲除引起的转录机制变化,并模拟A549细胞在小分子扰动后的单细胞轨迹。
原文摘要 · Abstract (English)
Single-cell data provide high-dimensional measurements of the transcriptional states of cells, but extracting insights into the regulatory functions of genes, particularly identifying transcriptional mechanisms affected by biological perturbations, remains a challenge. Many perturbations induce compensatory cellular responses, making it difficult to distinguish direct from indirect effects on gene regulation. Modeling how gene regulatory functions shape the temporal dynamics of these responses is key to improving our understanding of biological perturbations. Dynamical models based on differential equations offer a principled way to capture transcriptional dynamics, but their application to single-cell data has been hindered by computational constraints, stochasticity, sparsity, and noise. Existing methods either rely on low-dimensional representations or make strong simplifying assumptions, limiting their ability to model transcriptional dynamics at scale. We introduce a Functional and Learnable model of Cell dynamicS, FLeCS, that incorporates gene network structure into coupled differential equations to model gene regulatory functions. Given (pseudo)time-series single-cell data, FLeCS accurately infers cell dynamics at scale, provides improved functional insights into transcriptional mechanisms perturbed by gene knockouts, both in myeloid differentiation and K562 Perturb-seq experiments, and simulates single-cell trajectories of A549 cells following small-molecule perturbations.
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