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 group investigates the regulatory mechanisms and general principles underlying embryogenesis—the process by which an entire organism is generated from a single cell—using C. elegans as a model. Distinct from strategies used in classic developmental genetics, our focus is not a specific gene, pathway, or process. Instead, we treat individual cells as functional and regulatory units and apply systems biology strategies to investigate two principal questions: How does genome information specify cellular states? How do cellular states determine developmental functions? In pursuit of the answers to these questions, we employ a multidisciplinary approach including genetics, live imaging, functional genomics, phenomics, and systems biology. Our long-term goal is to understand the regulation of embryogenesis at the systems level.

 

C. elegans is the first multicellular organism to have its cell atlas completely mapped, including the lineage history, anatomy, and fate of all 959 somatic cells, along with quantitative cellular behaviors during embryogenesis. This cell atlas and powerful genetic tools make C. elegans a leading model organism to elucidate the regulation of cell differentiation at the single-cell and systems levels. However, whereas the cell atlas of development has been fully resolved, the molecular atlas of cell differentiation remains to be systematically elucidated. For example, we still lack comprehensive knowledge of the chromatin states, gene transcription, protein expression, molecular interactions, and regulatory networks within each developing cell; such knowledge is critical for the understanding, modeling, and engineering of cell fates. To fill this knowledge gap, we are applying a high-throughput imaging-based strategy to perform single-cell functional analysis of cellular regulatory states during embryogenesis. The method relies on long-term 3D time-lapse imaging of developing embryos followed by systematic cell lineage tracing and quantification of each cell's molecular and developmental behaviors, including cell proliferation, gene expression, differentiated state, and spatial position. This method provides a powerful tool with which to understand the regulatory basis of cell lineage and embryogenesis—to not only trace the dynamic gene expression and cellular states during development, but also to study their regulation based on systems-wide perturbation experiments.

 

In addition, we are interested in understanding the cellular basis of embryonic plasticity and robustness. Embryogenesis is a highly reproducible process by which individuals of a given species grow into morphologically and functionally equivalent organisms. An intriguing question is how is developmental reproducibility achieved and maintained in the presence of extensive molecular, cellular, and environmental variation? C. elegans is an excellent model for investigating developmental plasticity and robustness at the single-cell level, as its embryogenesis follows an invariant cell lineage to generate the same set of cells in precisely the same way. This reproducibility allows the straightforward identification of equivalent cells between individuals, and also allows cell-by-cell comparisons of phenotypes. Furthermore, the developmental behaviors of C. elegans cells are highly stereotypical, and this predictability makes analysis of the variability in cellular states and behaviors particularly meaningful and biologically relevant. We reason that a systems-level analysis of the sources, properties, and implications of developmental variability and plasticity will provide an important perspective for understanding the establishment and maintenance of developmental robustness.

 

The two main research interests in the lab are:

· Single-cell combinatorial regulatory code of transcription factors

· Cell-specific chromatin regulatory states

 

· Plasticity of cellular behaviors during embryogenesis

· Regulation of gene expression plasticity and noise

# Co-first author

* corresponding author

 

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*. Nature 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.

  

 

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)

 

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)