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Mbd3/NuRD controls lymphoid cell fate and inhibits tumorigenesis by repressing a B cell transcriptional program

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Loughran, SJ 
Comoglio, F 


Differentiation of lineage-committed cells from multipotent progenitors requires 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/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 towards 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 tumour formation.



Animals, B-Lymphocytes, Carcinogenesis, Cell Differentiation, Cell Lineage, DNA-Binding Proteins, Gene Expression Regulation, Lymphocytes, Lymphoma, T-Cell, Mi-2 Nucleosome Remodeling and Deacetylase Complex, Mice, Mice, Inbred C57BL, Multipotent Stem Cells, Thymocytes, Transcription Factors

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Journal of Experimental Medicine

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Rockefeller University Press
Cancer Research Uk (None)
Leukaemia & Lymphoma Research (7060)
Leukaemia & Lymphoma Research (12029)
Cancer Research UK (21762)
Cancer Research Uk (None)
MRC (MR/K500975/1)
Medical Research Council (MC_PC_12009)
Wellcome Trust (098021/Z/11/Z)
Medical Research Council (MR/M008975/1)
Wellcome Trust (100140/Z/12/Z)
Wellcome Trust (097922/Z/11/Z)
Leukaemia & Lymphoma Research (13003)
F.C. was supported by an EMBO long-term fellowship (1305-2015 and Marie Curie Actions LTFCOFUND2013/GA-2013-609409). Work in the Green lab is supported Cancer Research UK (grants refs. C1163/A12765 and C1163/A12526), Bloodwise (grant ref. 13003), and core support grants by the Wellcome Trust to the Cambridge Institute for Medical Research (100140/Z/12/Z) and Wellcome Trust-MRC Cambridge Stem Cell Institute (097922/Z/11/Z).