title: Decoding the regulatory network of early blood development from single-cell gene expression measurements.
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.
authors: Department of Haematology, Cambridge Institute for Medical Research, University of Cambridge, UK.|Wellcome Trust - Medical Research Council Cambridge Stem Cell Institute, University of Cambridge, Cambridge, UK.
authors: Victoria
authors: V
authors: Moignard
authors: Department of Haematology, Cambridge Institute for Medical Research, University of Cambridge, UK.|Wellcome Trust - Medical Research Council Cambridge Stem Cell Institute, University of Cambridge, Cambridge, UK.
authors: Steven
authors: S
authors: Woodhouse
authors: Institute of Computational Biology, Helmholtz Zentrum München, Neuherberg, Germany.|Department of Mathematics, Technische Universität München, Garching, Germany.
authors: Laleh
authors: L
authors: Haghverdi
authors: Cancer Research UK Stem Cell Haematopoiesis Group, Paterson Institute for Cancer Research, University of Manchester, Manchester, UK.
authors: Andrew J
authors: AJ
authors: Lilly
authors: Department of Haematology, Cambridge Institute for Medical Research, University of Cambridge, UK.|Wellcome Trust - Medical Research Council Cambridge Stem Cell Institute, University of Cambridge, Cambridge, UK.|Laboratory for Stem Cell Biology, RIKEN Center for Developmental Biology, Chuo-ku, Kobe, Japan.
authors: Yosuke
authors: Y
authors: Tanaka
authors: Department of Haematology, Cambridge Institute for Medical Research, University of Cambridge, UK.|Wellcome Trust - Medical Research Council Cambridge Stem Cell Institute, University of Cambridge, Cambridge, UK.
authors: Adam C
authors: AC
authors: Wilkinson
authors: Institute of Computational Biology, Helmholtz Zentrum München, Neuherberg, Germany.
authors: Florian
authors: F
authors: Buettner
authors: Sanger Institute-EBI Single Cell Genomics Centre, Wellcome Trust Sanger Institute, Hinxton, Cambridge, UK.
authors: Iain C
authors: IC
authors: Macaulay
authors: Department of Haematology, Cambridge Institute for Medical Research, University of Cambridge, UK.
authors: Wajid
authors: W
authors: Jawaid
authors: Department of Haematology, Cambridge Institute for Medical Research, University of Cambridge, UK.|Wellcome Trust - Medical Research Council Cambridge Stem Cell Institute, University of Cambridge, Cambridge, UK.
authors: Evangelia
authors: E
authors: Diamanti
authors: Laboratory for Stem Cell Biology, RIKEN Center for Developmental Biology, Chuo-ku, Kobe, Japan.
authors: Shin-Ichi
authors: SI
authors: Nishikawa
authors: Department of Computer Science, University of Leicester, Leicester, UK.
authors: Nir
authors: N
authors: Piterman
authors: Cancer Research UK Stem Cell Haematopoiesis Group, Paterson Institute for Cancer Research, University of Manchester, Manchester, UK.
authors: Valerie
authors: V
authors: Kouskoff
authors: Institute of Computational Biology, Helmholtz Zentrum München, Neuherberg, Germany.|Department of Mathematics, Technische Universität München, Garching, Germany.
authors: Fabian J
authors: FJ
authors: Theis
authors: Microsoft Research Cambridge, Cambridge, UK.|Department of Biochemistry, University of Cambridge, Cambridge, UK.
authors: Jasmin
authors: J
authors: Fisher
authors: Department of Haematology, Cambridge Institute for Medical Research, University of Cambridge, UK.|Wellcome Trust - Medical Research Council Cambridge Stem Cell Institute, University of Cambridge, Cambridge, UK.
authors: Berthold
authors: B
authors: Göttgens
mesh_terms: D000818:Animals; D001483:Base Sequence; D001773:Blood Cells / Q000378:metabolism*; D003198:Computer Simulation; D004058:Diffusion; D005260:Female; D054262:Gastrulation; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D053263:Gene Regulatory Networks; D008297:Male; D008813:Mice, Inbred ICR; D008957:Models, Genetic; D008969:Molecular Sequence Data; D059010:Single-Cell Analysis / Q000379:methods*; D014158:Transcription, Genetic