⏰ Analyzing cell-to-cell variability in time
Single-cell analysis tools have revolutionized many disciplines of biology. Yet, despite the growing single-cell data, we often lack a temporal view of how cells maintain homeostasis or how they respond to environmental signals at the individual cell level. Temporal analysis of single cells is critical for understanding the mode, mechanism, and function of cell-to-cell variability. We have been developing tools and techniques for analyzing cells in time, and have also integrated these tools with single-cell snapshot data (including single-cell RNA-seq/ATAC-seq). Through these efforts, we have provided dynamic perspectives on how and why cells are different in several examples. As we continue to analyze cells in time, we envision that a dynamic map of cells in various tissues and environments would help to elucidate fundamental principles underlying cell-to-cell variability.
🔍 Deciphering regulatory principles underlying cellular heterogeneity by profiling transcription factor dynamics
An important mechanism accounting for the variability among cells is the regulatory dynamics, particularly the activity dynamics of transcription factors (TFs). We have been interested in two areas of research related to TF dynamics: the profiling of TF dynamics across systems and conditions, and the functional roles of TF dynamics in development, differentiation, and immunity. Over the past few years, we have uncovered a new mode of gene regulation mediated by TF dynamics in budding yeast and have developed a new approach for profiling TF dynamics globally across hundreds of TFs. We are continuing to search for dynamic regulatory principles governing T cell immune responses and cancer cell state transitions with the hope of identifying new ways to modulate these processes.
🔍 Uncovering global regulatory mechanisms underlying cellular heterogeneity
While it has been widely recognized that cells are heterogeneous, even when they share the same genetic background, the source of such heterogeneity remains largely elusive. In addition to the gene-specific mechanisms (such as TF dynamics) that contribute to cell-to-cell variability in gene expression, we have been working on uncovering global regulatory mechanisms that contribute to cellular heterogeneity at the global scale. Such global regulatory mechanisms may play pivotal roles in conferring differential cancer drug resistance and differential developmental potential.
🔧 Toward robust and predictable cellular programming
Programming mammalian cells and tissues with synthetic biological devices faces two key challenges: 1) individual cells in a tissue are highly heterogeneous, exhibiting different responses to the same input; 2) synthetic devices often fail to operate as designed due to interferences from the host cell. We are working on addressing both challenges through data-driven rational design as well as high-throughput screening.