An experimentally validated network of nine haematopoietic transcription factors reveals mechanisms of cell state stability
- University Hospital Essen, Germany
- University of Cambridge, United Kingdom
- University of Oxford, United Kingdom
- Walter and Eliza Hall Institute of Medical Research, Australia
- University of Pennsylvania, United States
- VU University Amsterdam, Netherlands
Abstract
Transcription factor (TF) networks determine cell type identity by establishing and maintaining lineage-specific expression profiles, yet reconstruction of mammalian regulatory network models has been hampered by a lack of comprehensive functional validation of regulatory interactions. Here, we report comprehensive ChIP-Seq, transgenic and reporter gene experimental data that have allowed us to construct an experimentally validated regulatory network model for haematopoietic stem/progenitor cells (HSPCs). Model simulation coupled with subsequent experimental validation using single cell expression profiling revealed potential mechanisms for cell state stabilisation, and also how a leukemogenic TF fusion protein perturbs key HSPC regulators. The approach presented here should help to improve our understanding of both normal physiological and disease processes.
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Animal experimentation: All mice were housed in microisolator cages and provided continuously with sterile food, water, and bedding. All mice were kept in specified pathogen-free conditions, and all procedures were performed according to the United Kingdom Home Office regulations under project licence 70/8406
Copyright
© 2016, Schütte et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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An experimentally validated network of nine haematopoietic transcription factors reveals mechanisms of cell state stability
eLife 5:e11469.
https://doi.org/10.7554/eLife.11469
