Nat Cell Biol PMID: 23524953 (2013)
Characterization of transcriptional networks in blood stem and progenitor cells using high-throughput single-cell gene expression analysis.
Victoria Moignard1, Iain C. Macaulay2, Gemma Swiers3, Florian Buettner4, Judith Schütte1, Fernando J. Calero-Nieto1, Sarah Kinston1, Anagha Joshi1, Rebecca Hannah1, Fabian J. Theis4,5, Sten Eirik Jacobsen2, Marella F. de Bruijn3 and Berthold Göttgens1,6
Cellular decision-making is mediated by a complex interplay of external stimuli with the intracellular environment, in particular transcription factor regulatory networks. Here we have determined the expression of a network of 18 key haematopoietic transcription factors in 597 single primary blood stem and progenitor cells isolated from mouse bone marrow. We demonstrate that different stem/progenitor populations are characterized by distinctive transcription factor expression states, and through comprehensive bioinformatic analysis reveal positively and negatively correlated transcription factor pairings, including previously unrecognized relationships between Gata2, G1 and G1b. Validation using transcriptional and transgenic assays conrmed direct regulatory interactions consistent with a regulatory triad in immature blood stem cells, where Gata2 may function to modulate cross-inhibition between G1 and G1b. Single-cell expression proling therefore identies network states and allows reconstruction of network hierarchies involved in controlling stem cell fate choices, and provides a blueprint for studying both normal development and human disease.