Zhuo Du

1999-2003    B.S., Biotechnology, Hunan Agricultural University, Changsha, China

2003-2008    Ph.D., Biochemistry and Molecular Biology, China Agricultural University, Beijing, China

 

2003-2008    Ph.D., China Agricultural University, Beijing, China. Laboratory of Dr. Ning Li. Subject: Regulatory genomics of G4 DNA motifs

2008-2009    Postdoctoral Researcher, Albert Einstein College of Medicine, New York, U.S.A. Laboratory of Dr. Carl Schildkraut. Subject: Single-molecule analysis of DNA replication dynamics during cell differentiation

2009-2014    Postdoctoral Researcher, Memorial Sloan Kettering Cancer Center, New York, U.S.A. Laboratory of Dr. Zhirong Bao, Subject: Systems biology of C. elegans embryogenesis using live imaging-based phenotype analysis

 

2015-present  Group Leader, Institute of Genetics and Developmental Biology, Chinese Academy of Sciences, Beijing, China

 
Our team is dedicated to uncovering the intricacies of embryogenesis - the remarkable transformation of a single cell into a complete organism – through the lens of the C. elegans model. We adopt a cell-centric perspective on development, treating individual cells as functional and regulatory units, and employing systems biology strategies to decode the underlying regulatory mechanisms. Instead of focusing on specific genes, pathways, or processes, our research is driven by two core inquiries: How does genome information specify cellular states? And how do cellular states influence developmental functions? To tackle these questions, we utilize a multidisciplinary approach that integrates genetics, live-embryo imaging, functional genomics, phenomics, and systems biology. Our long-term goal is to understand the regulation of embryogenesis at the systems level.

 

C. elegans has achieved a landmark status as the first multicellular organism to have its entire cell atlas mapped. This atlas encompasses the developmental history, anatomy, and ultimate fate of all 959 somatic cells that make up the organism. With advanced genetic tools, C. elegans stands at the forefront of research into development regulation, facilitating in-depth studies at both the single-cell and whole-organism scales. Despite the comprehensive resolution of the developmental cell atlas, a systematic exploration of the molecular dynamics in developing cells remains to be accomplished. The existing gaps include a comprehensive knowledge of the chromatin states, gene transcription profiles, protein dynamics, molecular interactions, and regulatory networks within each cell during development. Gaining insights into these processes is crucial for understanding normal development, as well as modeling and engineering cell fates and functions in cell therapy.

To bridge this knowledge gap, our lab employs a high-throughput, imaging-based approach for conducting single-cell functional analysis of embryogenesis. This technique utilizes long-term 3D time-lapse imaging to record embryonic development, coupled with systematic cell lineage tracing and quantitative analyses. Such an approach enables accurate quantification of each cell’s molecular activities and developmental dynamics, including aspects such as proliferation, gene expression, differentiated state, and spatial positioning. By integrating this powerful technique with system-wide genetic perturbations, we aim to unravel the intricate molecular mechanisms governing embryogenesis.

· Novel single-cell methods to trace key regulatory events during embryogenesis

· Spatiotemporal patterning codes of developmental fates

· Regulation of developmental transition from multipotency to unipotency

 

Another intriguing aspect of embryogenesis is its remarkable robustness, which ensures individual embryos develop into morphologically and functionally consistent entities despite significant molecular, cellular, and environmental variation. Studies have unveiled critical molecular mechanisms that enhance the robustness of biological processes, including parallel pathways, stochastic expression variability, induced genetic compensations, and gene network topology. Although these molecular mechanisms shed light on how biological systems manage molecular noises, they fall short of directly explaining how developing systems tackle noise at the cellular level. Questions arise about how embryos deal with developmental noises at the cellular level, whether embryonic cells possess induced behavioral and functional plasticity as a means to buffer noise, and the role of cell-cell communication in achieving robust development.

C. elegans serves as a powerful model system to explore these questions, owing to its highly reproducible developmental processes. Its embryogenesis is characterized by an invariant cell lineage that produces an identical set of cells in the exact same manner across all individuals, allowing for the identification and comparison of equivalent cells and their phenotypes. Moreover, the predictability of the developmental behaviors of individual cells lends significant biological relevance to the study of cellular states and behavior noise. To gain a comprehensive understanding of developmental robustness across different scales, we employ C. elegans as the model to investigate how cellular-level mechanisms contribute to the robustness of multicellular developing systems.

· Contributions of cellular compensation to developmental robustness

· Genetic determinants of cellular plasticity

# Co-first author

* corresponding author

 

A lineage-resolved cartography of microRNA promoter activity in C. elegans empowers multidimensional developmental analysis. Xu W#, Liu J#, Qi H#, Si R, Zhao Z, Tao Z, Bai Y, Hu S, Sun X, Cong Y, Zhang H, Fan D, Xiao L, Wang Y, Li Y*, Du Z*. Nat Commun. 2024 Mar 30;15(1):2783 (1-23).

 

Spatiotemporal analysis of mRNA-protein relationships enhances transcriptome-based developmental inference. Fan D, Cong Y, Liu J, Zhang H, Du Z*. Cell Rep. 2024 Mar 26;43(3):113928 (1-23).

 

Defect-buffering cellular plasticity increases robustness of metazoan embryogenesis. Xiao L, Fan D, Qi H, Cong Y, Du Z*. Cell Syst. 2022 Aug 17;13(8):615-630.

 

A 4D single-cell protein atlas of transcription factors delineates spatiotemporal patterning during embryogenesis. Ma X#, Zhao Z#, Xiao L#, Xu W, Kou Y, Zhang Y, Wu G, Wang Y, Du Z*. Nat Methods. 2021 Aug;18(8):893-902.

Cover story and highlighted by News & Views.

 

Single-cell dynamics of chromatin activity during cell lineage differentiation in Caenorhabditis elegans embryos. Zhao Z#, Fan R#, Xu W, Kou Y, Wang Y, Ma X, Du Z*. Mol Syst Biol. 2021 Apr;17(4):e10075 (1-24).

 

Multivariable regulation of gene expression plasticity in metazoans. Xiao L#, Zhao Z#, He F*, Du Z*.Open Biol. 2019 Dec;9(12):190150 (1-16).

 

Systems properties and spatiotemporal regulation of cell position variability during embryogenesis.

Li X#, Zhao Z#, Xu W, Fan R, Xiao L, Ma X, Du Z*. Cell Rep. 2019 Jan 8;26(2):313-321.e7.

 

Trans-splicing enhances translational efficiency in C. elegans. Yang YF#, Zhang X#, Ma X#, Zhao T#, Sun Q, Huan Q, Wu S, Du Z*, Qian W*. Genome Res. 2017 Sep;27(9):1525-1535.

 

Digital development: a database of cell lineage differentiation in C. elegans with lineage phenotypes, cell-specific gene functions and a multiscale model. Santella A, Kovacevic I, Herndon LA, Hall DH, Du Z*, Bao Z*. Nucleic Acids Res. 2016 Jan 4;44(D1):D781-5.

 

The regulatory landscape of lineage differentiation in a metazoan embryo. Du Z*, Santella A, He F, Shah PK, Kamikawa Y, Bao Z*. Dev Cell. 2015 Sep 14;34(5):592-607.

 

E3 ubiquitin ligases promote progression of differentiation during C. elegans embryogenesis.

Du Z#, He F#, Yu Z, Bowerman B, Bao Z*. Dev Biol. 2015 Feb 15;398(2):267-79.

 

De novo inference of systems-level mechanistic models of development from live-imaging-based phenotype analysis. Du Z, Santella A, He F, Tiongson M, Bao Z*. Cell. 2014 Jan 16;156(1-2):359-72.

 

Systematic quantification of developmental phenotypes at single-cell resolution during embryogenesis. Moore JL, Du Z, Bao Z*. Development. 2013 Aug;140(15):3266-74.

 

Genome-wide colonization of gene regulatory elements by G4 DNA motifs. Du Z#, Zhao Y#, Li N*. Nucleic Acids Res. 2009 Nov;37(20):6784-98.

 

Genome-wide analysis reveals regulatory role of G4 DNA in gene transcription. Du Z#, Zhao Y#, Li N*.Genome Res. 2008 Feb;18(2):233-41.

  

 

Gene regulatory patterning codes in early cell fate specification of the C. elegans embryo. Cole AG#, Hashimshony T#, Du Z, Yanai I*. Elife. 2024 Jan 29;12:RP87099.

 

Metabolic plasticity sustains the robustness of Caenorhabditis elegans embryogenesis. Chen S, Su X, Zhu J, Xiao L, Cong Y, Yang L, Du Z, Huang X*. EMBO Rep. 2023 Dec 6;24(12):e57440.

 

Dynamic chromatin regulatory programs during embryogenesis of hexaploid wheat. Zhao L*, Yang Y, Chen J, Lin X, Zhang H, Wang H, Wang H, Bie X, Jiang J, Feng X, Fu X, Zhang X, Du Z, Xiao J*. Genome Biol. 2023 Jan 13;24(1):7.

 

Comparative Proteome and Cis-Regulatory Element Analysis Reveals Specific Molecular Pathways Conserved in Dog and Human Brains. Hong H#, Zhao Z#, Huang X, Guo C, Zhao H, Wang GD, Zhang YP, Zhao JP, Shi J, Wu QF, Jiang YH, Wang Y, Li LM, Du Z, Zhang YQ*, Xiong Y*. Mol Cell Proteomics. 2022 Aug;21(8):100261.

 

Dogs lacking Apolipoprotein E show advanced atherosclerosis leading to apparent clinical complications.Zhao H#, Zhao J#, Wu D#, Sun Z#, Hua Y, Zheng M, Liu Y, Yang Q, Huang X, Li Y, Piao Y, Wang Y, Lam SM, Xu H, Shui G, Wang Y, Yao H, Lai L, Du Z, Mi J*, Liu E*, Ji X*, Zhang YQ*. Sci China Life Sci. 2021 Oct 21.

 

Lineage context switches the function of a C. elegans Pax6 homolog in determining a neuronal fate. Brandt JP#, Rossillo M#, Du Z, Ichikawa D, Barnes K, Chen A, Noyes M, Bao Z, Ringstad N*. Development. 2019 Apr 15;146(8):dev168153.

 

mTOR regulates phase separation of PGL granules to modulate their autophagic degradation. Zhang G, Wang Z, Du Z, Zhang H*. Cell. 2018 Sep 6;174(6):1492-1506.e22.

 

POS-1 promotes endo-mesoderm development by inhibiting the cytoplasmic polyadenylation of neg-1 mRNA. Elewa A, Shirayama M, Kaymak E, Harrison PF, Powell DR, Du Z, Chute CD, Woolf H, Yi D, Ishidate T, Srinivasan J, Bao Z, Beilharz TH, Ryder SP, Mello CC*. Dev Cell. 2015 Jul 6;34(1):108-18.

 

A semi-local neighborhood-based framework for probabilistic cell lineage tracing. Santella A, Du Z, Bao Z*. BMC Bioinformatics. 2014 Jun 25;15:217.

 

Inverted selective plane illumination microscopy (iSPIM) enables coupled cell identity lineaging and neurodevelopmental imaging in Caenorhabditis elegans. Wu Y*, Ghitani A, Christensen R,Santella A, Du Z, Rondeau G, Bao Z, Colón-Ramos D, Shroff H. Proc Natl Acad Sci U S A. 2011 Oct 25;108(43):17708-13.

 

A hybrid blob-slice model for accurate and efficient detection of fluorescence labeled nuclei in 3D. Santella A, Du Z, Nowotschin S, Hadjantonakis AK, Bao Z*. BMC Bioinformatics. 2010 Nov 29;11:580.

 

Single-molecule analysis reveals changes in the DNA replication program for the POU5F1 locus upon human embryonic stem cell differentiation. Schultz SS, Desbordes SC, Du Z, Kosiyatrakul S, Lipchina I, Studer L, Schildkraut CL*. Mol Cell Biol. 2010 Sep;30(18):4521-34.

 

Extensive selection for the enrichment of G4 DNA motifs in transcriptional regulatory regions of warm blooded animals. Zhao Y#, Du Z#, Li N*. FEBS Lett. 2007 May 15;581(10):1951-6.

 

 

C. elegans strains donated to the Caenorhabditis Genetics Center (CGC)

 

single-cell CArtography of MicroRNA Expression based on Reporter Assay (scCAMERA) (Nature Communications 2024)

 

Single-cell Phenotypic Landscape of Embryonic Development in Conserved Genes (Cell Systems 2022)

 

4D Single-Cell Protein Atlas of Transcription Factors (Nature Methods 2021)

 

Single-cell chromatin activity landscape (Molecular Systems Biology 2021)

 

Cell position variability during early embryogenesis (Cell Reports 2019)

 

Single-cell phenomics of cell lineage differentiation following perturbing essential genes (Cell 2014 and Developmental Cell 2015)

 http://www.digital-development.org/ (Also available on WormAtlas)