High-throughput light-sheet microscopy and subcellular protein atlas

    For our ultimate goal of painting a proteome-wide map of endogenous proteins inside human cells, we are developing two techniques: (1) new split-protein-based fluorescent probles that enable large-scale labeling of endogenous proteins in human cell lines via gene editing, and (2) new light-sheet microscopes for high-resolution 3D live cell imaging. Combing these two technical advances, we are systematically analyzing the dynamic re-organization of various nuclear and cytoplasmic structures throughout the cell cycle.

Protein phase-separation and the compartmentation of cell signaling

    Cell signaling networks are the basis of cellular activities and, ultimately, the everyday life of an organism. As the activities in a signaling network are often highly dynamic in time and heterogeneous in space, with the same signaling molecule functioning differently among cellular compartments, we take a microscopy-based approach to map the localization and activities of endogenous signaling components. We are particularly interested in understanding how cytoplasmic protein granules organize cancer cell singaling in the RTK-RAS-MAPK signaling pathway.

Super-resolution microscopy and macromolecular complex architectures

     Modern structural biology methods, such as X-ray crystallography, NMR and cryoEM, are powerful tools to determine the structure of biomolecules ranging from small proteins to large complexes. However, it is still a major challenge to connect these in vitro isolated structures to their native cellular counterparts. We are developing a new approach based on super-resolution optical microscopy to characterize the architecture of molecular complexes in situ. In particular, we are advancing the technologies of Stochastic Optical Reconstruction Microscopy (STORM), expansion microscopy (ExM) as well as computational analysis methods to achieve molecular-scale resolution in localizing specific protein components within a complex. We are interested in studying ciliary transition zone and other subcellular structures.

Genome engineering and the spatial organization of the genome

     With our ever expanding knowledge on the genome from DNA sequencing, it is now clear that mechanisms regulating the functional output of the genome go far beyond its linear sequence. The packaging of the chromatin, its dynamic interactions with proteins and RNAs, and modifications to histones all play important roles during organism development, environment adaptation and cancer formation. For this purpose, we take the "imagenomics" approach, developing new tools to visualize the dynamics of specific genomic elements and their epigenetic status in living cells. These techniques will perfectly complement sequencing-based approaches and fundamentally advance our ability to understand the regulation of genome function. Highlights of our recent work include the development of the CRISPR imaging technology for endogenous gene loci.

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