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Interactions between lineage-associated transcription factors govern haematopoietic progenitor states.

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Wilson, Nicola K 
Hannah, Rebecca 
Kinston, Sarah J 
Cauchy, Pierre 


Recent advances in molecular profiling provide descriptive datasets of complex differentiation landscapes including the haematopoietic system, but the molecular mechanisms defining progenitor states and lineage choice remain ill-defined. Here, we employed a cellular model of murine multipotent haematopoietic progenitors (Hoxb8-FL) to knock out 39 transcription factors (TFs) followed by RNA-Seq analysis, to functionally define a regulatory network of 16,992 regulator/target gene links. Focussed analysis of the subnetworks regulated by the B-lymphoid TF Ebf1 and T-lymphoid TF Gata3 revealed a surprising role in common activation of an early myeloid programme. Moreover, Gata3-mediated repression of Pax5 emerges as a mechanism to prevent precocious B-lymphoid differentiation, while Hox-mediated activation of Meis1 suppresses myeloid differentiation. To aid interpretation of large transcriptomics datasets, we also report a new method that visualises likely transitions that a progenitor will undergo following regulatory network perturbations. Taken together, this study reveals how molecular network wiring helps to establish a multipotent progenitor state, with experimental approaches and analysis tools applicable to dissecting a broad range of both normal and perturbed cellular differentiation landscapes.



haematopoiesis, network, progenitors, scRNA-Seq, transcription factor, Animals, Cell Differentiation, Cell Lineage, Epigenomics, GATA3 Transcription Factor, Hematopoiesis, Hematopoietic Stem Cell Transplantation, Hematopoietic System, Mice, Myeloid Ecotropic Viral Integration Site 1 Protein, PAX5 Transcription Factor, Precursor Cells, B-Lymphoid, Transcription Factors

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Springer Science and Business Media LLC


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Wellcome Trust (206328/Z/17/Z)
Bloodwise (18002)
Medical Research Council (MR/S036113/1)
Wellcome Trust (203151/Z/16/Z)
Cancer Research UK (21762)
National Institute of Diabetes and Digestive and Kidney Diseases (R24DK106766)
Medical Research Council (MC_PC_12009)
Cancer Research UK (A25117)
Wellcome Trust, MRC, CRUK, Blood Cancer UK, National Institutes of Health