Journal
JOURNAL OF EXPERIMENTAL MEDICINE
Volume 214, Issue 10, Pages 3085-3104Publisher
ROCKEFELLER UNIV PRESS
DOI: 10.1084/jem.20161827
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Funding
- European Molecular Biology Organization long-term fellowship [1305-2015, LTF COF UND2013/GA2013-609409]
- Cancer Research UK [C1163/A12765, C1163/A12526]
- Bloodwise [13003]
- Wellcome Trust [100140/Z/12/Z]
- Wellcome Trust-MRC Cambridge Stem Cell Institute [097922/Z/11/Z]
- MRC [MC_UU_12009/5, G0801073, MC_UU_00016/5, MR/M008975/1, MR/L006340/1, MR/M00919X/1, G0501838] Funding Source: UKRI
- Cancer Research UK [21762, 12765] Funding Source: researchfish
- Medical Research Council [MC_UU_00016/5, MC_UU_12009/5, MR/M008975/1, MR/M00919X/1, G0801073, G0501838, MR/L006340/1, MC_PC_12009, 1581868] Funding Source: researchfish
- National Institute for Health Research [ACF-2016-14-006] Funding Source: researchfish
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Differentiation of lineage-committed cells from multipotent progenitors requires the establishment of accessible chromatin at lineage-specific transcriptional enhancers and promoters, which is mediated by pioneer transcription factors that recruit activating chromatin remodeling complexes. Here we show that the Mbd3/nucleosome remodeling and deacetylation (NuRD) chromatin remodeling complex opposes this transcriptional pioneering during B cell programming of multipotent lymphoid progenitors by restricting chromatin accessibility at B cell enhancers and promoters. Mbd3/NuRD-deficient lymphoid progenitors therefore prematurely activate a B cell transcriptional program and are biased toward overproduction of pro-B cells at the expense of T cell progenitors. The striking reduction in early thymic T cell progenitors results in compensatory hyperproliferation of immature thymocytes and development of T cell lymphoma. Our results reveal that Mbd3/NuRD can regulate multilineage differentiation by constraining the activation of dormant lineage-specific enhancers and promoters. In this way, Mbd3/NuRD protects the multipotency of lymphoid progenitors, preventing B cell-programming transcription factors from prematurely enacting lineage commitment. Mbd3/NuRD therefore controls the fate of lymphoid progenitors, ensuring appropriate production of lineage-committed progeny and suppressing tumor formation.
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