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

Détails

Ressource 1Télécharger: BIB_212DBCD34BB9.P001.pdf (971.03 [Ko])
Etat: Public
Version: de l'auteur
ID Serval
serval:BIB_212DBCD34BB9
Type
Article: article d'un périodique ou d'un magazine.
Collection
Publications
Titre
Hard-wired heterogeneity in blood stem cells revealed using a dynamic regulatory network model.
Périodique
Bioinformatics
Auteur(s)
Bonzanni N., Garg A., Feenstra K.A., Schütte J., Kinston S., Miranda-Saavedra D., Heringa J., Xenarios I., Göttgens B.
ISSN
1367-4811 (Electronic)
ISSN-L
1367-4803
Statut éditorial
Publié
Date de publication
2013
Volume
29
Numéro
13
Pages
i80-i88
Langue
anglais
Résumé
MOTIVATION: 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.
RESULTS: 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 INFORMATION: Supplementary data are available at Bioinformatics online.
Mots-clé
Animals, Cell Line, Erythrocytes/cytology, Gene Regulatory Networks, Genes, Regulator, Hematopoiesis/genetics, Hematopoietic Stem Cells/cytology, Hematopoietic Stem Cells/metabolism, Mice, Models, Genetic, Transcription Factors/metabolism
Pubmed
Web of science
Open Access
Oui
Création de la notice
12/02/2014 17:22
Dernière modification de la notice
20/08/2019 12:57
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