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Nat Biotechnol. 2015 Mar;33(3):269-276. doi: 10.1038/nbt.3154. Epub 2015 Feb 9.

Decoding the regulatory network of early blood development from single-cell gene expression measurements.

Author information

1
Department of Haematology, Cambridge Institute for Medical Research, University of Cambridge, UK.
2
Wellcome Trust - Medical Research Council Cambridge Stem Cell Institute, University of Cambridge, Cambridge, UK.
3
Institute of Computational Biology, Helmholtz Zentrum München, Neuherberg, Germany.
4
Department of Mathematics, Technische Universität München, Garching, Germany.
5
Cancer Research UK Stem Cell Haematopoiesis Group, Paterson Institute for Cancer Research, University of Manchester, Manchester, UK.
6
Laboratory for Stem Cell Biology, RIKEN Center for Developmental Biology, Chuo-ku, Kobe, Japan.
7
Sanger Institute-EBI Single Cell Genomics Centre, Wellcome Trust Sanger Institute, Hinxton, Cambridge, UK.
8
Department of Computer Science, University of Leicester, Leicester, UK.
9
Microsoft Research Cambridge, Cambridge, UK.
10
Department of Biochemistry, University of Cambridge, Cambridge, UK.
#
Contributed equally

Abstract

Reconstruction of the molecular pathways controlling organ development has been hampered by a lack of methods to resolve embryonic progenitor cells. Here we describe a strategy to address this problem that combines gene expression profiling of large numbers of single cells with data analysis based on diffusion maps for dimensionality reduction and network synthesis from state transition graphs. Applying the approach to hematopoietic development in the mouse embryo, we map the progression of mesoderm toward blood using single-cell gene expression analysis of 3,934 cells with blood-forming potential captured at four time points between E7.0 and E8.5. Transitions between individual cellular states are then used as input to develop a single-cell network synthesis toolkit to generate a computationally executable transcriptional regulatory network model of blood development. Several model predictions concerning the roles of Sox and Hox factors are validated experimentally. Our results demonstrate that single-cell analysis of a developing organ coupled with computational approaches can reveal the transcriptional programs that underpin organogenesis.

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PMID:
25664528
PMCID:
PMC4374163
DOI:
10.1038/nbt.3154
[Indexed for MEDLINE]
Free PMC Article

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