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PMID: 25664528 Published · ppublish English Journal Article Research Support, Non-U.S. Gov't

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

Nature biotechnology ·Vol. 33 ·No. 3 ·2015-03-00 ·Pages 269-276

Moignard V, Woodhouse S, Haghverdi L, Lilly AJ, Tanaka Y, Wilkinson AC, Buettner F, Macaulay IC, Jawaid W, Diamanti E, Nishikawa SI, Piterman N, Kouskoff V, Theis FJ, Fisher J, Göttgens B

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.

MeSH Terms
Animals Base Sequence Blood Cells/metabolism Computer Simulation Diffusion Female Gastrulation Gene Expression Profiling Gene Expression Regulation Gene Regulatory Networks Male Mice, Inbred ICR Models, Genetic Molecular Sequence Data Single-Cell Analysis/methods Transcription, Genetic
Authors & Affiliations
16 authors, click to expand affiliations / ORCID
Moignard Victoria
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.
Woodhouse Steven
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.
Haghverdi Laleh
Institute of Computational Biology, Helmholtz Zentrum München, Neuherberg, Germany. | Department of Mathematics, Technische Universität München, Garching, Germany.
Lilly Andrew J
Cancer Research UK Stem Cell Haematopoiesis Group, Paterson Institute for Cancer Research, University of Manchester, Manchester, UK.
Tanaka Yosuke
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.
Wilkinson Adam C
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.
Buettner Florian
Institute of Computational Biology, Helmholtz Zentrum München, Neuherberg, Germany.
Macaulay Iain C
Sanger Institute-EBI Single Cell Genomics Centre, Wellcome Trust Sanger Institute, Hinxton, Cambridge, UK.
Jawaid Wajid
Department of Haematology, Cambridge Institute for Medical Research, University of Cambridge, UK.
Diamanti Evangelia
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.
Nishikawa Shin-Ichi
Laboratory for Stem Cell Biology, RIKEN Center for Developmental Biology, Chuo-ku, Kobe, Japan.
Piterman Nir
Department of Computer Science, University of Leicester, Leicester, UK.
Kouskoff Valerie
Cancer Research UK Stem Cell Haematopoiesis Group, Paterson Institute for Cancer Research, University of Manchester, Manchester, UK.
Theis Fabian J
Institute of Computational Biology, Helmholtz Zentrum München, Neuherberg, Germany. | Department of Mathematics, Technische Universität München, Garching, Germany.
Fisher Jasmin
Microsoft Research Cambridge, Cambridge, UK. | Department of Biochemistry, University of Cambridge, Cambridge, UK.
Göttgens Berthold
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.
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Article Info
Journal
Nature biotechnology
Abbr.
Nat Biotechnol
ISSN
1546-1696
DOI
10.1038/nbt.3154
Published
2015-03-00
Epub
2015-00-09
Pages
269-276
Language
English
Region
United States
NLM ID
9604648
PMCID
PMC4374163
Subset
IM
Grants
Cancer Research UK · 12765 · United Kingdom
Medical Research Council · G0900951 · United Kingdom
Wellcome Trust · 097922 · United Kingdom
Medical Research Council · MR/M008975/1 · United Kingdom
Wellcome Trust · 100140 · United Kingdom
Medical Research Council · MC_PC_12009 · United Kingdom
Biotechnology and Biological Sciences Research Council · BB/I00050X/1 · United Kingdom
Databases
GEO
GSE61470
Corrections
CommentIn
PMID: 25748916
External Links
PubMed source DOI: 10.1038/nbt.3154 PMC Full Text View journal details
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