Siyuan (Steven) Wang, PhD
Research & Publications
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).
Extensive Research Description
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).
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.
Biophysics; Biotechnology; Carcinoma; Cell Nucleus; Chromatin; Cell Biology; DNA; Enhancer Elements, Genetic; Embryonic and Fetal Development; Gene Expression Regulation; Genetics; Mutation; Stem Cells; Genome; Computational Biology; Chromosome Structures; Genomics; Chromatin Assembly and Disassembly; Transcriptome; Inventions; CRISPR-Cas Systems; Diseases
- New mechanism of chromatin compartmentalization by BRD2.Cheng Y, Wang S. New mechanism of chromatin compartmentalization by BRD2. Trends In Genetics : TIG 2022 PMID: 35811175, DOI: 10.1016/j.tig.2022.06.016.
- PYME: an integrated platform for high-throughput nanoscopyBarentine A, Lin Y, Courvan E, Kidd P, Liu M, Balduf L, Phan T, Rivera-Molina F, Grace M, Marin Z, Chen J, Wang S, Neugebauer K, Baddeley D, Bewersdorf J. PYME: an integrated platform for high-throughput nanoscopy Biophysical Journal 2022, 121: 137a. DOI: 10.1016/j.bpj.2021.11.2009.
- TAD-like single-cell domain structures exist on both active and inactive X chromosomes and persist under epigenetic perturbationsCheng Y, Liu M, Hu M, Wang S. TAD-like single-cell domain structures exist on both active and inactive X chromosomes and persist under epigenetic perturbations Genome Biology 2021, 22: 309. PMID: 34749781, PMCID: PMC8574027, DOI: 10.1186/s13059-021-02523-8.
- Spatial transcriptome profiling by MERFISH reveals fetal liver hematopoietic stem cell niche architectureLu Y, Liu M, Yang J, Weissman SM, Pan X, Katz SG, Wang S. Spatial transcriptome profiling by MERFISH reveals fetal liver hematopoietic stem cell niche architecture Cell Discovery 2021, 7: 47. PMID: 34183665, PMCID: PMC8238952, DOI: 10.1038/s41421-021-00266-1.
- Chromatin tracing and multiplexed imaging of nucleome architectures (MINA) and RNAs in single mammalian cells and tissueLiu M, Yang B, Hu M, Radda JSD, Chen Y, Jin S, Cheng Y, Wang S. Chromatin tracing and multiplexed imaging of nucleome architectures (MINA) and RNAs in single mammalian cells and tissue Nature Protocols 2021, 16: 2667-2697. PMID: 33903756, PMCID: PMC9007104, DOI: 10.1038/s41596-021-00518-0.
- ProbeDealer is a convenient tool for designing probes for highly multiplexed fluorescence in situ hybridizationHu M, Yang B, Cheng Y, Radda JSD, Chen Y, Liu M, Wang S. ProbeDealer is a convenient tool for designing probes for highly multiplexed fluorescence in situ hybridization Scientific Reports 2020, 10: 22031. PMID: 33328483, PMCID: PMC7745008, DOI: 10.1038/s41598-020-76439-x.
- Chromatin Tracing: Imaging 3D Genome and NucleomeHu M, Wang S. Chromatin Tracing: Imaging 3D Genome and Nucleome Trends In Cell Biology 2020, 31: 5-8. PMID: 33191055, PMCID: PMC8094612, DOI: 10.1016/j.tcb.2020.10.006.
- Multiplexed imaging of nucleome architectures in single cells of mammalian tissueLiu M, Lu Y, Yang B, Chen Y, Radda JSD, Hu M, Katz SG, Wang S. Multiplexed imaging of nucleome architectures in single cells of mammalian tissue Nature Communications 2020, 11: 2907. PMID: 32518300, PMCID: PMC7283333, DOI: 10.1038/s41467-020-16732-5.
- Lamina-Dependent Stretching and Unconventional Chromosome Compartments in Early C. elegans EmbryosSawh AN, Shafer MER, Su JH, Zhuang X, Wang S, Mango SE. Lamina-Dependent Stretching and Unconventional Chromosome Compartments in Early C. elegans Embryos Molecular Cell 2020, 78: 96-111.e6. PMID: 32105612, PMCID: PMC7263362, DOI: 10.1016/j.molcel.2020.02.006.
- Super-Resolution Fluorescence Imaging of Spatial Organization of Proteins and Lipids in Natural RubberWu J, Qu W, Huang G, Wang S, Huang C, Liu H. Super-Resolution Fluorescence Imaging of Spatial Organization of Proteins and Lipids in Natural Rubber Biomacromolecules 2017, 18: 1705-1712. PMID: 28463484, DOI: 10.1021/acs.biomac.6b01827.
- Spatial organization of chromatin domains and compartments in single chromosomesWang S, Su JH, Beliveau BJ, Bintu B, Moffitt JR, Wu CT, Zhuang X. Spatial organization of chromatin domains and compartments in single chromosomes Science 2016, 353: 598-602. PMID: 27445307, PMCID: PMC4991974, DOI: 10.1126/science.aaf8084.
- An RNA-aptamer-based two-color CRISPR labeling systemWang S, Su JH, Zhang F, Zhuang X. An RNA-aptamer-based two-color CRISPR labeling system Scientific Reports 2016, 6: 26857. PMID: 27229896, PMCID: PMC4882555, DOI: 10.1038/srep26857.
- Spatial organization shapes the turnover of a bacterial transcriptomeMoffitt JR, Pandey S, Boettiger AN, Wang S, Zhuang X. Spatial organization shapes the turnover of a bacterial transcriptome ELife 2016, 5: e13065. PMID: 27198188, PMCID: PMC4874777, DOI: 10.7554/elife.13065.
- Super-resolution imaging reveals distinct chromatin folding for different epigenetic statesBoettiger AN, Bintu B, Moffitt JR, Wang S, Beliveau BJ, Fudenberg G, Imakaev M, Mirny LA, Wu CT, Zhuang X. Super-resolution imaging reveals distinct chromatin folding for different epigenetic states Nature 2016, 529: 418-422. PMID: 26760202, PMCID: PMC4905822, DOI: 10.1038/nature16496.
- Spatially resolved, highly multiplexed RNA profiling in single cellsChen KH, Boettiger AN, Moffitt JR, Wang S, Zhuang X. Spatially resolved, highly multiplexed RNA profiling in single cells Science 2015, 348: aaa6090. PMID: 25858977, PMCID: PMC4662681, DOI: 10.1126/science.aaa6090.
- Characterization and development of photoactivatable fluorescent proteins for single-molecule–based superresolution imagingWang S, Moffitt JR, Dempsey GT, Xie XS, Zhuang X. Characterization and development of photoactivatable fluorescent proteins for single-molecule–based superresolution imaging Proceedings Of The National Academy Of Sciences Of The United States Of America 2014, 111: 8452-8457. PMID: 24912163, PMCID: PMC4060684, DOI: 10.1073/pnas.1406593111.
- Modeling spatial correlation of DNA deformation: DNA allostery in protein binding.Xu X, Ge H, Gu C, Gao YQ, Wang SS, Thio BJ, Hynes JT, Xie XS, Cao J. Modeling spatial correlation of DNA deformation: DNA allostery in protein binding. The Journal Of Physical Chemistry. B 2013, 117: 13378-87. PMID: 23795567, PMCID: PMC3808477, DOI: 10.1021/jp4047243.
- Probing Allostery Through DNAKim S, Broströmer E, Xing D, Jin J, Chong S, Ge H, Wang S, Gu C, Yang L, Gao YQ, Su XD, Sun Y, Xie XS. Probing Allostery Through DNA Science 2013, 339: 816-819. PMID: 23413354, PMCID: PMC3586787, DOI: 10.1126/science.1229223.
- Cell Shape Can Mediate the Spatial Organization of the Bacterial CytoskeletonWang S, Wingreen NS. Cell Shape Can Mediate the Spatial Organization of the Bacterial Cytoskeleton Biophysical Journal 2013, 104: 541-552. PMID: 23442905, PMCID: PMC3566457, DOI: 10.1016/j.bpj.2012.12.027.
- The mechanics of shape in prokaryotes.Wang S, Shaevitz JW. The mechanics of shape in prokaryotes. Frontiers In Bioscience-Scholar 2013, 5: 564-74. PMID: 23277069, DOI: 10.2741/s390.
- Helical insertion of peptidoglycan produces chiral ordering of the bacterial cell wallWang S, Furchtgott L, Huang KC, Shaevitz JW. Helical insertion of peptidoglycan produces chiral ordering of the bacterial cell wall Proceedings Of The National Academy Of Sciences Of The United States Of America 2012, 109: e595-e604. PMID: 22343529, PMCID: PMC3309786, DOI: 10.1073/pnas.1117132109.
- The bacterial actin MreB rotates, and rotation depends on cell-wall assemblyvan Teeffelen S, Wang S, Furchtgott L, Huang KC, Wingreen NS, Shaevitz JW, Gitai Z. The bacterial actin MreB rotates, and rotation depends on cell-wall assembly Proceedings Of The National Academy Of Sciences Of The United States Of America 2011, 108: 15822-15827. PMID: 21903929, PMCID: PMC3179079, DOI: 10.1073/pnas.1108999108.
- Mechanics, dynamics and organization of the bacterial cytoskeleton and cell wall.Siyuan Wang, Ph. D. Dissertation, Princeton University, (2011).
- Actin-like cytoskeleton filaments contribute to cell mechanics in bacteriaWang S, Arellano-Santoyo H, Combs PA, Shaevitz JW. Actin-like cytoskeleton filaments contribute to cell mechanics in bacteria Proceedings Of The National Academy Of Sciences Of The United States Of America 2010, 107: 9182-9185. PMID: 20439764, PMCID: PMC2889055, DOI: 10.1073/pnas.0911517107.
- Measuring the bending stiffness of bacterial cells using an optical trap.Wang S, Arellano-Santoyo H, Combs PA, Shaevitz JW. Measuring the bending stiffness of bacterial cells using an optical trap. Journal Of Visualized Experiments 2010 PMID: 20421864, PMCID: PMC3164081, DOI: 10.3791/2012.
- Modelling the SOS response by semi-stochastic simulation.Ming Ni*, Siyuan Wang*, and Qi Ouyang, Chinese Physics Letters, Vol. 25, No. 7, 2702-2705, (2008). *Co-first authors.
- Simulating the temporal modulation of inducible DNA damage response in Escherichia coli.Ni M, Wang SY, Li JK, Ouyang Q. Simulating the temporal modulation of inducible DNA damage response in Escherichia coli. Biophysical Journal 2007, 93: 62-73. PMID: 17434938, PMCID: PMC1914449, DOI: 10.1529/biophysj.106.090712.
- Stochastic model of coliphage lambda regulatory networkWang S, Zhang Y, Ouyang Q. Stochastic model of coliphage lambda regulatory network Physical Review E 2006, 73: 041922. PMID: 16711851, DOI: 10.1103/physreve.73.041922.