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PMID: 23813012 Published · ppublish English Journal Article Research Support, Non-U.S. Gov't

Hard-wired heterogeneity in blood stem cells revealed using a dynamic regulatory network model.

Bioinformatics (Oxford, England) ·Vol. 29 ·No. 13 ·2013-07-01 ·Pages i80-8

Bonzanni N, Garg A, Feenstra KA, Schütte J, Kinston S, Miranda-Saavedra D, Heringa J, Xenarios I, Göttgens B

Abstract

Combinatorial interactions of transcription factors with cis-regulatory elements control the dynamic progression through successive cellular states and thus underpin all metazoan development. The construction of network models of cis-regulatory elements, therefore, has the potential to generate fundamental insights into cellular fate and differentiation. Haematopoiesis has long served as a model system to study mammalian differentiation, yet modelling based on experimentally informed cis-regulatory interactions has so far been restricted to pairs of interacting factors. Here, we have generated a Boolean network model based on detailed cis-regulatory functional data connecting 11 haematopoietic stem/progenitor cell (HSPC) regulator genes. Despite its apparent simplicity, the model exhibits surprisingly complex behaviour that we charted using strongly connected components and shortest-path analysis in its Boolean state space. This analysis of our model predicts that HSPCs display heterogeneous expression patterns and possess many intermediate states that can act as 'stepping stones' for the HSPC to achieve a final differentiated state. Importantly, an external perturbation or 'trigger' is required to exit the stem cell state, with distinct triggers characterizing maturation into the various different lineages. By focusing on intermediate states occurring during erythrocyte differentiation, from our model we predicted a novel negative regulation of Fli1 by Gata1, which we confirmed experimentally thus validating our model. In conclusion, we demonstrate that an advanced mammalian regulatory network model based on experimentally validated cis-regulatory interactions has allowed us to make novel, experimentally testable hypotheses about transcriptional mechanisms that control differentiation of mammalian stem cells. Supplementary data are available at Bioinformatics online.

MeSH Terms
Animals Cell Line Erythrocytes/cytology Gene Regulatory Networks Genes, Regulator Hematopoiesis/genetics Hematopoietic Stem Cells/cytology,metabolism Mice Models, Genetic Transcription Factors/metabolism
Chemicals
Transcription Factors
Authors & Affiliations
9 authors, click to expand affiliations / ORCID
Bonzanni Nicola
IBIVU Centre for Integrative Bioinformatics, VU University Amsterdam, AIMMS Amsterdam Institute for Molecules Medicines and Systems, VU University Amsterdam, De Boelelaan 1081, NKI-AVL The Netherlands.
Garg Abhishek
Feenstra K Anton
Schütte Judith
Kinston Sarah
Miranda-Saavedra Diego
Heringa Jaap
Xenarios Ioannis
Göttgens Berthold
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Article Info
Journal
Bioinformatics (Oxford, England)
Abbr.
Bioinformatics
ISSN
1367-4811
DOI
10.1093/bioinformatics/btt243
Published
2013-07-01
Pages
i80-8
Language
English
Region
England
NLM ID
9808944
PMCID
PMC3694641
Subset
IM
Grants
Wellcome Trust · 079249 · United Kingdom
National Centre for the Replacement, Refinement and Reduction of Animals in Research · G0900729/1 · United Kingdom
Cancer Research UK · 12765 · United Kingdom
Wellcome Trust · 100140 · United Kingdom
Medical Research Council · MC_PC_12009 · United Kingdom
External Links
PubMed source DOI: 10.1093/bioinformatics/btt243 PMC Full Text View journal details
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