Computational Modeling of Lineage Decisions using Single-cell Data

项目摘要 细胞分化是复杂的多细胞生物体的一个基本生物学过程。 从单细胞胚胎发育而来，并在一生中保持组织动态平衡。单元格整合来自 并将它们传递给下游的转录调控因子，后者执行表达 而染色质的变化定义了分化轨迹中的表型状态转变。澄清 细胞如何选择自己的命运，以及它们走的道路，这是该领域的一个重大挑战。 单细胞(Sc)RNA测序技术正在彻底改变我们对细胞空间- 形成分化的时间轨迹。出现额外的高吞吐量、多式联运 配对RNA和atac-seq、sccut&tag和空间技术等技术提供了前所未有的 有机会将机械性的见解提取到低于分化轨迹的世系决策中。 这项提议旨在通过开发复杂的新算法来挖掘这一巨大的潜力，该算法将 用于模拟和解释复杂生物学的单细胞测量。通过分析多个单细胞RNA- SEQ数据集，我们证明了表型不对称性是谱系决定的普遍特征。我们会 开发算法以揭示驱动谱系决策的机制和潜在的不对称性 三个大的研究方向。我们将研究：(I)增强子启动和转录的作用 调节，(Ii)开放和异染色质动力学，和(Iii)形成分化中的细胞通讯 轨迹。我们的研究将带来关于细胞自主和非自主的新见解 当细胞在表型格局中导航时，它们参与的机制。成功完成这项工作 研究将提供一个强有力的机制基础来描述正常的分化事件， 疾病中这些机制的失调，理解伤口分化机制的重新用途 修复和再生，并重建体内和体外的分化过程，以解锁治疗 细胞工程的潜力。

Project Summary Cellular differentiation is a fundamental biological process through which complex multi-cellular organisms develop from single-cell embryos and maintain tissue homeostasis throughout life. Cells integrate signals from the microenvironment and transmit them to downstream transcriptional regulators, which execute the expression and chromatin changes to define phenotypic state transitions in differentiation trajectories. Elucidating the principles of how cells choose their fate, and the path they take to get there, is a major challenge in the field. Single-cell (sc) RNA sequencing technologies are revolutionizing our understanding of the cellular spatio- temporal trajectories that shape differentiation. The emergence of additional high throughput, multimodal technologies such as paired RNA&ATAC-seq, scCUT&Tag and spatial technologies provide unprecedented opportunities to extract mechanistic insights into the lineage decisions that underly differentiation trajectories. This proposal aims to exploit this enormous potential by developing sophisticated new algorithms that integrate single-cell measurements to model and interpret complex biology. Through analysis of multiple single-cell RNA- seq datasets, we demonstrate that phenotypic asymmetries are a pervasive feature of lineage decisions. We will develop algorithms to unravel the mechanisms that drive lineage decisions and the underlying asymmetries in three broad research directions. We will investigate the role of: (i) enhancer priming and transcriptional regulation, (ii) open and heterochromatin dynamics, and (iii) cell communication in shaping differentiation trajectories. Our studies will lead to novel insights surrounding cell-autonomous and non-autonomous mechanisms engaged by cells as they navigate the phenotypic landscape. Successful completion of this research will provide a robust mechanistic basis to delineate normal differentiation events, decipher dysregulation of these mechanisms in disease, understand repurposing of differentiation mechanisms in wound healing and regeneration, and reconstruct differentiation processes in vivo and ex vivo to unlock the therapeutic potential of cell engineering.