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Development and function of mammalian tissues and organs depend on the behaviors and dynamics of individual cells. The Cao lab investigates how a cell population in a mammalian body maintains homeostasis and how it is disrupted in cancer and aging-related disorders. They develop genomic techniques to profile and perturb cell dynamics at single-cell resolution.

Individual cells are the fundamental unit of form and function in biological systems. A delicately balanced program of cell proliferation, differentiation, and apoptosis ensures that tissues and organs can maintain a stable size and function throughout life. Disruption of this homeostasis can lead to disorders such as cancer and neurodegenerative diseases.

The Cao lab seeks to characterize various aspects of single-cell biology in order to better understand how tissues and organs maintain stable populations of cells. For this goal, the lab creates techniques to comprehensively profile how cell state changes over time in vivo, as well as study how cells shape and are shaped by their surrounding environments.

Cao and colleagues have developed several exponentially scalable technologies for profiling gene expression and other genomic features at single-cell resolution. One of these, called sci-RNA-seq, allows researchers to routinely profile more than two million individual cells at once. Another tool, called sci-CAR, concurrently profiles how gene expression and the epigenome—the molecular instructions that dictate which genes can be read—change in tandem. A third method, known as sci-fate, captures transcriptional dynamics by distinguishing newly synthesized transcripts in each cell. Cao has applied these techniques to achieve global, organism-scale views of cell state heterogeneity in worms, mice, and humans, yielding insights into gene regulation underlying cell population dynamics across main developmental lineages.

The function of mammalian organs is maintained by the behavior and dynamics of individual cells. However, nearly all existing technologies for profiling complex mammalian tissues fail to capture cell dynamics in real-time. Cao’s lab works to expand the current toolbox to quantitatively profile cell behaviors such as cellular proliferation, migration, or apoptosis, and couple them with complex genomic features as well as cell-environment interactions in each of thousands to millions of single cells. The lab will use these methods to explore how a cell population changes in cancer and aging-related diseases, and they will dissect the internal and external forces driving cell fate determination.

Although current single-cell genomic techniques enable increasingly comprehensive profiling of cell states, there are no effective strategies for manipulating cell states and population dynamics in vivo. Another goal of the Cao lab is to develop methods for cell type-specific manipulation and investigate the rules governing cell population robustness in the human body. His lab is identifying, validating, and optimizing cell-type-specific regulatory modules, such as compact combinations of enhancers and promoters that together direct gene expression in a cell type-specific manner. They aim to leverage this knowledge to develop tools that enhance cell population robustness or restore cell population homeostasis in cancer and aging-related disorders.