Siyuan (Steven) Wang, PhD

Research in Wang Lab focuses on the development and application of state-of-the-art imaging-based omics approaches to understand the spatial organization of mammalian genome and transcriptome, and how they impact cellular states. Recent advances include the development of the first-in-kind image-based 3D genomics method termed chromatin tracing to trace the spatial folding of genome, co-development of MERFISH for spatial transcriptome profiling (See Nature Methods Method of the Year 2020), and the development of MINA to measure multiscale chromatin folding, copy numbers of numerous RNA species, and associations of numerous genomic regions with nuclear landmarks in the same, single cells in mammalian tissue (Science 2016, Science 2015, Molecular Cell, 2020, Nature Communications 2020, Trends in Cell Biology 2020, Nature Protocols 2021, Cell Discovery 2021).

From chromatin tracing to MINA

Wang’s research interest is to understand the spatiotemporal complexity of molecular and cellular systems, and how the complexity affects biological functions. Especially, he aims to understand the spatial organization of mammalian chromatin – the complex of genomic DNA and associated proteins. The spatial organization of chromatin in the nucleus is of critical importance to many essential genomic functions, from the regulation of gene expression to the replication of the genome. Unfortunately, relatively little is known about the three-dimensional (3D) organization of chromatin beyond the length scale of the nucleosomes, in large part due to the lack of tools that allow direct visualization of the 3D folding of chromatin in individual chromosomes. To address this need, his main postdoctoral work (Science, 2016) involved the development of a first-in-kind, advanced DNA imaging method termed “chromatin tracing“, via multiplexed sequential fluorescence in situ hybridization (FISH). This novel method enabled direct spatial tracing of numerous genomic regions in individual chromosomes in single cells, offering a powerful tool to study the 3D folding of chromatin. As the first application of this method, he studied the spatial organization of the recently discovered topologically associating domains (TADs), also termed contact domains, by tracing the 3D positions of TADs in individual chromosomes in interphase human cells, and revealed a series of unexpected structural features. This work opened up many opportunities to study the spatial organization of chromatin at different length scales in a variety of important biological processes and in diseases. He also co-developed a highly-multiplexed RNA FISH technique termed “MERFISH” that enabled localized detection and quantification of 1000 different RNA species in a single cell (Science, 2015). In comparison to single-cell RNA sequencing, this multiplexed FISH method easily retains the spatial information of all the probed transcripts, and is highly sensitive for counting low-copy-number transcripts. Additionally, he led the development of a new photoactivatable fluorescent protein (PAFP), named mMaple3 (PNAS, 2014), that outperforms previously existing PAFPs in single-molecule-based superresolution imaging (STORM/PALM) and has been adopted by hundreds of research labs around the world, and an RNA-aptamer-based two-color CRISPR labeling system for studying chromatin dynamics (Scientific Reports, 2016).

Recently, his independent lab at Yale University introduced a new integrative technique, termed Multiplexed Imaging of Nucleome Architectures (MINA). This technique enabled measurements of multiscale chromatin folding, copy numbers of numerous RNA species, and associations of numerous genomic regions with nuclear lamina, nucleoli and surface of chromosomes in the same, single cells in mammalian tissue. For the first time, this development allowed the joint analysis of the multiscale and multi-faceted 3D nucleome organization including promoter-enhancer interactions, chromatin domains, compartments, chromosome territories, and associations with nuclear lamina and nucleoli in the same, single cells and in different cell types in mammalian tissue sections. Applying the MINA technique to mouse fetal liver, this work identified de novo cell-type-specific chromatin architectures associated with gene expression, as well as chromatin organization principles independent of cell type (Nature Communications, 2020, bioRxiv, 2019; Nature Protocols, 2021).

Wang Lab aims to further develop the next generation of spatial omics technologies and to use our advanced toolkit to answer previously intractable biomedical questions in a variety of areas (Trends in Cell Biology, 2020; Scientific Reports 2020; Cell Discovery 2021).

Earlier research

As a graduate student at Princeton University, Wang studied bacterial cell mechanics, especially how the bacterial cytoskeleton coordinates cell wall synthesis. The first project (PNAS, 2010) in his dissertation showed that the bacterial actin homologue MreB contributes nearly as much to the rigidity of an E. coli cell as the peptidoglycan cell wall. This conclusion provided the premise for several theoretical works that assumed MreB applies force to the cell wall during growth, and suggested an evolutionary origin of cytoskeleton-governed cell rigidity. His second project (PNAS, 2011) dealt with the discovery of the motion of E. coli MreB linked to cell wall synthesis. This was the first observation of a cell-wall assembly driven molecular motor in bacteria. (Simultaneously with the work, Garner et al and Dominguez-Escobar et al discovered the same phenomenon in B. subtilis.) His third project (PNAS, 2012) elucidated that both cell wall synthesis and the peptidoglycan network have a chiral ordering, which is established by MreB. This work linked the molecular structures of the cytoskeleton and of the cell wall with organismal-scale behavior. His fourth project (Biophysical Journal, 2013) developed a generic, quantitative model to explain the various spatial patterns adopted by bacterial cytoskeletal proteins. The model set up a new theoretical framework for the study of membrane-polymer interaction, and is useful for the exploration of the physical limits of cytoskeleton organization.