Interactions between lineage-associated transcription factors govern haematopoietic progenitor states.
The EMBO journal
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Kucinski, I., Wilson, N., Hannah, R., Kinston, S., Cauchy, P., Lenaerts, A., Grosschedl, R., & et al. (2020). Interactions between lineage-associated transcription factors govern haematopoietic progenitor states.. The EMBO journal, e104983. https://doi.org/10.15252/embj.2020104983
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 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 program. 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 visualizes 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.
Wellcome Trust, MRC, CRUK, Blood Cancer UK, National Institutes of Health
Wellcome Trust (206328/Z/17/Z)
Wellcome Trust (203151/Z/16/Z)
Cancer Research UK (21762)
National Institutes of Health (NIH) (via Pennsylvania State University) (R24DK106766)
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External DOI: https://doi.org/10.15252/embj.2020104983
This record's URL: https://www.repository.cam.ac.uk/handle/1810/310104
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