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  Interactions between lineage-associated transcription factors govern haematopoietic progenitor states

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, 39: e104983. doi:10.15252/embj.2020104983.

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Kucinski.pdf (Publisher version), 5MB
 
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Online ahead of print

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 Creators:
Kucinski, Iwo1, Author
Wilson, Nicola K1, Author
Hannah, Rebecca1, Author
Kinston, Sarah J1, Author
Cauchy, Pierre2, Author              
Lenaerts, Aurelie2, Author
Grosschedl, Rudolf2, Author              
Göttgens, Berthold1, Author
Affiliations:
1External Organizations, ou_persistent22              
2Department of Cellular and Molecular Immunology, Max Planck Institute of Immunobiology and Epigenetics, Max Planck Society, ou_2243641              

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Free keywords: haematopoiesis; network; progenitors; scRNA-Seq; transcription factor
 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.

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Language(s): eng - English
 Dates: 2020-10-26
 Publication Status: Published online
 Pages: -
 Publishing info: -
 Table of Contents: -
 Rev. Type: Peer
 Identifiers: DOI: 10.15252/embj.2020104983
 Degree: -

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Title: The EMBO Journal
Source Genre: Journal
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Publ. Info: Nature Publishing Group
Pages: - Volume / Issue: 39 Sequence Number: e104983 Start / End Page: - Identifier: ISSN: 0261-4189
CoNE: https://pure.mpg.de/cone/journals/resource/954925497061_1