基于单细胞转录组数据揭示细胞命运决定的综合机制

Each cell makes independent fate decisions by integrating a wide array of signals from other cells and executing a complex choreography of gene-regulatory changes. Revealing the mechanisms of cell fate decisions is not only a challenge but also a key for understanding complex cell processes. Single-cell transcriptome data provide unprecedented opportunities for this study. Aiming at limitations of previous works that studied the single mechanisms of cell fate decisions from the separate viewpoints of cell and gene expression regulation, this project will use the combined method of statistical physics and information theory to study the systemic mechanisms of cell fate decisions from the three different levels of cell lineage (macroscopic), gene regulatory network (mesoscopic) and transcriptional bursting dynamics (microscopic). It will emphatically study how pseudo-temporal trajectories of cell progress (including all possible single and bifurcating trajectories) are reconstructed, how dynamic cell lineages (including determining transition probabilities and directions between cell linages) are built, how dynamic regulatory networks of key genes deciding cell fates are inferred, and how transcriptional bursting kinetics along the pseudo-trajectories are inferred, based on single-cell RNA-seq data. Through these studies, we tries to uncover the integrative mechanisms of cell fate decisions’ dynamic processes from stationary single-cell transcriptome data.

每个细胞都是通过整合各种信号和程序化遗传指令做出独立命运决定的。揭示细胞命运决定的机制既是一项挑战也是理解复杂细胞演化过程的关键，而单细胞转录组数据为这种研究提供了史无前例的机会。针对细胞命运决定的传统研究仅专注于细胞层面或基因表达调控层面的单一机制的局限，本项目拟应用统计物理学和信息论相结合的方法，从细胞谱系（宏观）、基因调控网（介观）和基因转录爆发动力学（微观）这三个不同层面来系统研究细胞命运决定的机制。将重点研究基于单细胞RNA测序数据，如何重构细胞演化过程的伪暂态轨迹（包括单轨、二分枝轨和多分枝轨等）；如何构建沿着伪细胞轨迹的动态细胞谱系（包括确定不同细胞类型间的转移概率和转移方向）；如何构建决定细胞命运的（沿着伪细胞轨迹的）动态关键基因调控网络；以及如何推断沿着伪细胞轨迹的关键基因转录爆发动力学。通过这些研究，试图从静态的单细胞转录组数据揭示出动态的细胞命运决定过程的综合机制。

每个细胞都是通过整合各种信号和程序化遗传指令做出独立命运决定的。揭示细胞命运决定的机制既是一项挑战也是理解复杂细胞演化过程的关键，而单细胞转录组数据为这种研究提供了史无前例的机会。针对细胞命运决定的传统研究仅专注于细胞层面或基因表达调控层面的单一机制的局限，本项目拟应用统计物理学和信息论相结合的方法，从细胞谱系（宏观）、基因调控网（介观）和基因转录爆发动力学（微观）这三个不同层面来系统研究细胞命运决定的机制。将重点研究基于单细胞RNA测序数据，如何重构细胞演化过程的伪暂态轨迹（包括单轨、二分枝轨和多分枝轨等）；如何构建沿着伪细胞轨迹的动态细胞谱系（包括确定不同细胞类型间的转移概率和转移方向）；如何构建决定细胞命运的（沿着伪细胞轨迹的）动态关键基因调控网络；以及如何推断沿着伪细胞轨迹的关键基因转录爆发动力学。通过这些研究，试图从静态的单细胞转录组数据揭示出动态的细胞命运决定过程的综合机制。