Siyuan (Steven) Wang, PhD
Research & Publications
Biography
News
Research Summary
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 "Best of 2021", Nature Protocols 2021, Cell Discovery 2021, Genome Biology 2021, Science Advances 2023). Most recently, the lab reported the first single-cell 3D genome atlas of any cancer, and developed the first ultra-high-content, multi-scale 3D genome regulator screen platform (bioRxiv 2023a, bioRxiv 2023b).
Extensive Research Description
Image-based 3D genomics and spatial multi-omics
At Harvard: 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 multiplexed DNA imaging method termed “chromatin tracing“, via 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).
At Yale: Wang’s independent lab at Yale is devoted to understand mammalian genome architectures and spatial transcriptome in health and disease. In the past few years, the lab introduced a new integrative technique, termed Multiplexed Imaging of Nucleome Architectures (MINA) – the first comprehensive image-based 3D nucleomics technique (Nat Comm 2020; Nat Protoc 2021). This method enabled multi-omic and multiscale visualization of single-cell nucleome architectures and gene expression to functionally define promoter-enhancer interactions, chromatin domains, compartments, territories, and chromatin interactions with nuclear landmarks in the same single cells of complex mammalian tissues. In applying the technique to mouse fetal liver, the team discovered cell-type-specific chromatin architectures associated with gene expression, chromatin organization principles independent of cell type, novel cell-cell interaction patterns, and underlying signalling mechanisms (Nat Comm 2020; Cell Discov 2021). They also applied chromatin tracing to study 3D chromatin changes in early C. elegans embryos (Molecular Cell 2020), and to elucidate novel architectures and their regulation in the folding conformations of the two copies of X chromosomes in female human cells (Genome Biology 2021; Science Advances 2023). Overall, the chromatin tracing and MINA technologies have revolutionized 3D genomics and multi-omics studies (Trends in Cell Biology “Best of 2021”).
Most recently, the team resolved the first single-cell 3D genome atlas of any cancer with genome-wide chromatin tracing, and identified an unexpected 3D genome bottleneck during subclonal lung tumor evolution in the native tissue microenvironment. They further defined key regulator and effector genes upstream and downstream of substantial 3D genome reorganization that drives histologic progression. This work, for the first time, charted a comprehensive blueprint of 3D genome alterations during cancer progression in the native tissue context and systematically revealed functional mechanisms of cancer evolution embedded in the rich information of single-cell 3D chromatin conformations (bioRxiv 2023a). It is expected that applying this approach broadly will have an enormous impact on understanding the epigenetic basis of cancer in situ and will lead to the development of novel diagnostic, prognostic, and therapeutic biomarkers based on the 3D genome. In another recent work, to systematically discover novel regulators of 3D genome, the team developed the first ultra-high-content, high-throughput, 3D genome regulator screening technology (bioRxiv 2023b). This development uniquely integrated real-3D genomics by chromatin tracing, pooled CRISPR screen, and a novel cellular barcoding and in situ decoding technique (BARC-FISH). It enabled efficient discovery of regulators of 3D genome architectures across a wide range of length scales and laid the foundation for a complete mapping of the 3D genomic regulatome, which may lead to a new avenue of therapeutics by halting or reversing the deleterious 3D genome reorganization in aging and diseases.
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.
Coauthors
Research Interests
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
Selected Publications
- Regulation of gene editing using T-DNA concatenation.Dickinson L, Yuan W, LeBlanc C, Thomson G, Wang S, Jacob Y. Regulation of gene editing using T-DNA concatenation. Nat Plants 2023 PMID: 37653336, DOI: 10.1038/s41477-023-01495-w.
- Female naïve human pluripotent stem cells carry X chromosomes with Xa-like and Xi-like folding conformations.Patterson B, Yang B, Tanaka Y, Kim KY, Cakir B, Xiang Y, Kim J, Wang S, Park IH. Female naïve human pluripotent stem cells carry X chromosomes with Xa-like and Xi-like folding conformations. Sci Adv 2023, 9: eadf2245. PMID: 37540754, DOI: 10.1126/sciadv.adf2245.
- 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, Lessard M, Rios Chen J, Wang S, Neugebauer K, Bewersdorf J, Baddeley D. An integrated platform for high-throughput nanoscopy Nature Biotechnology 2023, 1-8. PMID: 36914886, DOI: 10.1038/s41587-023-01702-1.
- Live imaging reveals chromatin compaction transitions and dynamic transcriptional bursting during stem cell differentiation in vivoMay D, Yun S, Gonzalez D, Park S, Chen Y, Lathrop E, Cai B, Xin T, Zhao H, Wang S, Gonzalez L, Cockburn K, Greco V. Live imaging reveals chromatin compaction transitions and dynamic transcriptional bursting during stem cell differentiation in vivo ELife 2023, 12: e83444. PMID: 36880644, PMCID: PMC10027315, DOI: 10.7554/elife.83444.
- NIH SenNet Consortium to map senescent cells throughout the human lifespan to understand physiological healthLee P, Benz C, Blood P, Börner K, Campisi J, Chen F, Daldrup-Link H, De Jager P, Ding L, Duncan F, Eickelberg O, Fan R, Finkel T, Furman D, Garovic V, Gehlenborg N, Glass C, Heckenbach I, Joseph Z, Katiyar P, Kim S, Königshoff M, Kuchel G, Lee H, Lee J, Ma J, Ma Q, Melov S, Metis K, Mora A, Musi N, Neretti N, Passos J, Rahman I, Rivera-Mulia J, Robson P, Rojas M, Roy A, Scheibye-Knudsen M, Schilling B, Shi P, Silverstein J, Suryadevara V, Xie J, Wang J, Wong A, Niedernhofer L, Wang S, Anvari H, Balough J, Benz C, Bons J, Brenerman B, Evans W, Gerencser A, Gregory H, Hansen M, Justice J, Kapahi P, Murad N, O’Broin A, Pavone M, Powell M, Scott G, Shanes E, Shankaran M, Verdin E, Winer D, Wu F, Adams A, Blood P, Bueckle A, Cao-Berg I, Chen H, Davis M, Filus S, Hao Y, Hartman A, Hasanaj E, Helfer J, Herr B, Joseph Z, Molla G, Mou G, Puerto J, Quardokus E, Ropelewski A, Ruffalo M, Satija R, Schwenk M, Scibek R, Shirey W, Sibilla M, Welling J, Yuan Z, Bonneau R, Christiano A, Izar B, Menon V, Owens D, Phatnani H, Smith C, Suh Y, Teich A, Bekker V, Chan C, Coutavas E, Hartwig M, Ji Z, Nixon A, Dou Z, Rajagopal J, Slavov N, Holmes D, Jurk D, Kirkland J, Lagnado A, Tchkonia T, Abraham K, Dibattista A, Fridell Y, Howcroft T, Jhappan C, Montes V, Prabhudas M, Resat H, Taylor V, Kumar M, Suryadevara V, Cigarroa F, Cohn R, Cortes T, Courtois E, Chuang J, Davé M, Domanskyi S, Enninga E, Eryilmaz G, Espinoza S, Gelfond J, Kirkland J, Kuchel G, Kuo C, Lehman J, Aguayo-Mazzucato C, Meves A, Rani M, Sanders S, Thibodeau A, Tullius S, Ucar D, White B, Wu Q, Xu M, Yamaguchi S, Assarzadegan N, Cho C, Hwang I, Hwang Y, Xi J, Adeyi O, Aliferis C, Bartolomucci A, Dong X, DuFresne-To M, Ikramuddin S, Johnson S, Nelson A, Niedernhofer L, Revelo X, Trevilla-Garcia C, Sedivy J, Thompson E, Robbins P, Wang J, Aird K, Alder J, Beaulieu D, Bueno M, Calyeca J, Chamucero-Millaris J, Chan S, Chung D, Corbett A, Gorbunova V, Gowdy K, Gurkar A, Horowitz J, Hu Q, Kaur G, Khaliullin T, Lafyatis R, Lanna S, Li D, Ma A, Morris A, Muthumalage T, Peters V, Pryhuber G, Reader B, Rosas L, Sembrat J, Shaikh S, Shi H, Stacey S, Croix C, Wang C, Wang Q, Watts A, Gu L, Lin Y, Rabinovitch P, Sweetwyne M, Artyomov M, Ballentine S, Chheda M, Davies S, DiPersio J, Fields R, Fitzpatrick J, Fulton R, Imai S, Jain S, Ju T, Kushnir V, Link D, Ben Major M, Oh S, Rapp D, Rettig M, Stewart S, Veis D, Vij K, Wendl M, Wyczalkowski M, Craft J, Enninful A, Farzad N, Gershkovich P, Halene S, Kluger Y, VanOudenhove J, Xu M, Yang J, Yang M. NIH SenNet Consortium to map senescent cells throughout the human lifespan to understand physiological health Nature Aging 2022, 2: 1090-1100. PMID: 36936385, PMCID: PMC10019484, DOI: 10.1038/s43587-022-00326-5.
- New mechanism of chromatin compartmentalization by BRD2Cheng Y, Wang S. New mechanism of chromatin compartmentalization by BRD2 Trends In Genetics 2022, 38: 1197-1198. PMID: 35811175, DOI: 10.1016/j.tig.2022.06.016.
- 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.