Our research program focuses on developing and applying state-of-the-art chemical and genomic analysis tools to chart cellular RNAs from birth to death and understand how the RNA life cycle is shaped and regulated in time and space to serve biological functions. In parallel, we aim to translate our understanding of RNA-centered gene regulation principles to design and engineer next-generation RNA drugs by expanding the alphabet, structure, and topology of synthetic RNAs to enhance their translation efficiency, stability, and tunability.
The intricate network of cell functions relies on gene expression programs, where information flows from DNA through RNA to protein. At the core of this process lies the RNA life cycle, which deciphers both the protein-coding and regulatory DNA sequences, ensuring protein products are synthesized in the right place at the right time. However, a few fundamental questions remain to be answered:
(1) Deciphering RNA Properties: Why do different genes exhibit drastic variations in RNA stability, location, and translation efficiency? What are the underlying chemical, physical, and biological foundations governing RNA properties inside cells?
(2) RNA-Centered Regulation: How does RNA-centered gene regulation contribute to the precise spatiotemporal control of protein production within cells and tissues? Can we manipulate the RNA life cycle to reprogram cell fates and states?
(3) Unraveling Disease Mechanisms: To what extent can RNA-centered regulation shed light on the characterization and understanding of human diseases? Can we develop improved treatments by intervening in the RNA life cycle?
(4) Synthetic RNA life cycle: Is it possible to reconstitute and redesign RNA metabolism and translation pathways with endogenous-level spatiotemporal accuracy and tunability?
(5) Next-Generation RNA drugs: Can we create synthetic mRNA constructs that surpass natural counterparts in terms of translation efficiency and RNA stability by orders of magnitudes, paving the way for transformative RNA-based therapies?
To fill those knowledge gaps, we first need a panoramic view of the whole mRNA life cycle directly within intact cells and tissues, encompassing synthesis, processing, transport, translation, and degradation, which is currently obscured by limited analytical tools. To overcome such challenges, our research aims to enable novel spatiotemporal measurements at unprecedented resolution and scale using in situ sequencing to probe and perturb the intricate dynamics of the RNA life cycle. Beyond mapping the RNA life cycle in health and disease, I also seek to translate our knowledge of post-transcriptional gene regulation mechanisms into next-generation RNA vectors and drugs by expanding and engineering the alphabet and topology of synthetic RNAs with unnatural chemical modifications.
We use a variety of synthetic and analytical approaches, such as nucleic acid chemistry, organic synthesis, polymer engineering, microscopy, optogenetics, electrophysiology, and computation. The lab members typically work in one or more types of lab space: chemical/biochemical bench, tissue culture room, microscope room, animal facility, and computational workstation.