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EBF1 primes B-lymphoid enhancers and limits the myeloid bias in murine multipotent progenitors

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

Deboutte,  Ward
Max Planck Institute of Immunobiology and Epigenetics, Max Planck Society;

Derecka,  Marta
Department of Cellular and Molecular Immunology, Max Planck Institute of Immunobiology and Epigenetics, Max Planck Society;

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

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Manke,  Thomas
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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10.1084_jem.20212437.pdf
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Lenaerts, A., Kucinski, I., Deboutte, W., Derecka, M., Cauchy, P., Manke, T., et al. (2022). EBF1 primes B-lymphoid enhancers and limits the myeloid bias in murine multipotent progenitors. Journal of Experimental Medicine, 219: e20212437. doi:10.1084/jem.20212437.


Cite as: https://hdl.handle.net/21.11116/0000-000B-0732-5
Abstract
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Article|September 01 2022
EBF1 primes B-lymphoid enhancers and limits the myeloid bias in murine multipotent progenitors
Aurelie Lenaerts
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, Iwo Kucinski
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, Ward Deboutte
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, Marta Derecka
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, Pierre Cauchy
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, Thomas Manke
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, Berthold Göttgens
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, Rudolf Grosschedl
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Author and Article Information
J Exp Med (2022) 219 (11): e20212437.
https://doi.org/10.1084/jem.20212437
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Hematopoietic stem cells (HSCs) and multipotent progenitors (MPPs) generate all cells of the blood system. Despite their multipotency, MPPs display poorly understood lineage bias. Here, we examine whether lineage-specifying transcription factors, such as the B-lineage determinant EBF1, regulate lineage preference in early progenitors. We detect low-level EBF1 expression in myeloid-biased MPP3 and lymphoid-biased MPP4 cells, coinciding with expression of the myeloid determinant C/EBPα. Hematopoietic deletion of Ebf1 results in enhanced myelopoiesis and reduced HSC repopulation capacity. Ebf1-deficient MPP3 and MPP4 cells exhibit an augmented myeloid differentiation potential and a transcriptome with an enriched C/EBPα signature. Correspondingly, EBF1 binds the Cebpa enhancer, and the deficiency and overexpression of Ebf1 in MPP3 and MPP4 cells lead to an up- and downregulation of Cebpa expression, respectively. In addition, EBF1 primes the chromatin of B-lymphoid enhancers specifically in MPP3 cells. Thus, our study implicates EBF1 in regulating myeloid/lymphoid fate bias in MPPs by constraining C/EBPα-driven myelopoiesis and priming the B-lymphoid fate.