An experimentally validated network of nine haematopoietic transcription factors reveals mechanisms of cell state stability.
Schütte J., Wang H., Antoniou S., Jarratt A., Wilson NK., Riepsaame J., Calero-Nieto FJ., Moignard V., Basilico S., Kinston SJ., Hannah RL., Chan MC., Nürnberg ST., Ouwehand WH., Bonzanni N., de Bruijn MF., Göttgens B.
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 leukaemogenic TF fusion protein perturbs key HSPC regulators. The approach presented here should help to improve our understanding of both normal physiological and disease processes.