Peng Qiangwei, Qiu Xiaojie, Li Tiejun
LMAM and School of Mathematical Sciences, Peking University, Beijing, China.
Department of Genetics, Stanford University School of Medicine, Stanford, California, United States of America.
PLoS Comput Biol. 2024 Nov 18;20(11):e1012606. doi: 10.1371/journal.pcbi.1012606. eCollection 2024 Nov.
The time-resolved scRNA-seq (tscRNA-seq) provides the possibility to infer physically meaningful kinetic parameters, e.g., the transcription, splicing or RNA degradation rate constants with correct magnitudes, and RNA velocities by incorporating temporal information. Previous approaches utilizing the deterministic dynamics and steady-state assumption on gene expression states are insufficient to achieve favorable results for the data involving transient process. We present a dynamical approach, Storm (Stochastic models of RNA metabolic-labeling), to overcome these limitations by solving stochastic differential equations of gene expression dynamics. The derivation reveals that the new mRNA sequencing data obeys different types of cell-specific Poisson distributions when jointly considering both biological and cell-specific technical noise. Storm deals with measured counts data directly and extends the RNA velocity methodology based on metabolic labeling scRNA-seq data to transient stochastic systems. Furthermore, we relax the constant parameter assumption over genes/cells to obtain gene-cell-specific transcription/splicing rates and gene-specific degradation rates, thus revealing time-dependent and cell-state-specific transcriptional regulations. Storm will facilitate the study of the statistical properties of tscRNA-seq data, eventually advancing our understanding of the dynamic transcription regulation during development and disease.
时间分辨单细胞RNA测序(tscRNA-seq)通过纳入时间信息,提供了推断具有物理意义的动力学参数的可能性,例如具有正确量级的转录、剪接或RNA降解速率常数,以及RNA速度。以前利用基因表达状态的确定性动力学和稳态假设的方法,对于涉及瞬态过程的数据不足以取得良好结果。我们提出了一种动力学方法,即Storm(RNA代谢标记的随机模型),通过求解基因表达动力学的随机微分方程来克服这些限制。推导表明,当同时考虑生物和细胞特异性技术噪声时,新的mRNA测序数据服从不同类型的细胞特异性泊松分布。Storm直接处理测量的计数数据,并将基于代谢标记scRNA-seq数据的RNA速度方法扩展到瞬态随机系统。此外,我们放宽了对基因/细胞的恒定参数假设,以获得基因-细胞特异性转录/剪接速率和基因特异性降解速率,从而揭示时间依赖性和细胞状态特异性转录调控。Storm将有助于研究tscRNA-seq数据的统计特性,最终推动我们对发育和疾病期间动态转录调控的理解。