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Interactions between lineage-associated transcription factors govern haematopoietic progenitor states

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Cauchy,  Pierre
Department of Cellular and Molecular Immunology, Max Planck Institute of Immunobiology and Epigenetics, Max Planck Society;

Lenaerts,  Aurelie
Department of Cellular and Molecular Immunology, Max Planck Institute of Immunobiology and Epigenetics, Max Planck Society;

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Grosschedl,  Rudolf
Department of Cellular and Molecular Immunology, Max Planck Institute of Immunobiology and Epigenetics, Max Planck Society;

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Citation

Kucinski, I., Wilson, N. K., Hannah, R., Kinston, S. J., Cauchy, P., Lenaerts, A., et al. (2020). Interactions between lineage-associated transcription factors govern haematopoietic progenitor states. The EMBO Journal, e104983. doi:10.15252/embj.2020104983.


Cite as: http://hdl.handle.net/21.11116/0000-0007-70F4-7
Abstract
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.