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

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.