Bioinformatics; corresponding author: I.Xenarios

Bioinformatics. 2013 Jul 1;29(13):i80-i88.

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


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 Cancer Institute, Plesmanlaan 121, Amsterdam, NBIC Netherlands Bioinformatics Centre, Geert Grooteplein 28, Nijmegen, The Netherlands, Swiss Institute of Bioinformatics, Quartier Sorge-Batiment Genopode, Lausanne, Switzerland, Cambridge Institute for Medical Research and Wellcome Trust and MRC Cambridge Stem Cell Institute, University of Cambridge, Hills Road, Cambridge, UK.



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.

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