Mechanisms and determinants of dynamic gene regulation during development and cellular differentiation

项目总结 人类基因组编码的信息规定了整个有机体的发育，包括 至少10万亿个细胞和200多种不同的细胞类型。基因组也包含引导信息 对一系列环境刺激做出适当反应，以维持动态平衡和应对挑战， 例如来自微生物病原体。对这一准则的修改或对其解释的失调几乎是所有这些行为的基础 人类疾病，包括慢性炎症性疾病、代谢紊乱和癌症。获取 从机制和数量上理解个体细胞中的基因调控是至关重要的 这是更好地了解疾病并最终治疗疾病的先决条件。研究基因调控 由于人体组织细胞的异质性以及大多数 人体样本不能进行纵向观测和直接扰动。然而，即将到来的 单细胞基因组技术、人IPSC的发展和基于有机物的体外模型 系统，以及强大的遗传干扰工具的可用，有可能克服这些 挑战和革命性的生物医学研究。在这项建议中，我们结合了单项- 细胞多组学工具，可以准确地描述单个细胞或分子内的多种调节功能 机制和以疾病为中心的研究，以了解基因和环境扰动是如何 调控过程扰乱了细胞分化，并构成了病理基础。

PROJECT SUMMARY The human genome encodes information that specifies the development of an entire organism comprising at least 10 trillion cells and more than 200 different cell types. The genome also contains the information to direct appropriate responses to a host of environmental stimuli to maintain homeostasis and respond to challenges, e.g. from microbial pathogens. Changes to this code or dysregulation of its interpretation underlie almost all human diseases, including chronic inflammatory diseases, metabolic disorders, and cancer. Obtaining mechanistic and quantitative understanding of gene regulation in individual cells is a crucial prerequisite for a better understanding, and ultimately treatment, of diseases. Studying gene regulatory processes in human tissues has been challenging because of their cellular heterogeneity and because most human samples are not accessible to longitudinal observations and direct perturbations. However, the advent of single cell genomic technologies, the development of human iPSC and organoid-based in vitro model systems, and the availability of powerful tools for genetic perturbations have the potential to overcome these challenges and to revolutionize biomedical research. In this proposal we combine the development of single- cell multiomic tools that accurately profile multiple regulatory features within single cells or molecules with mechanistic and disease-focused studies to understand how genetic and environmental perturbations of gene regulatory processes disrupt cellular differentiation and underlie pathologies.