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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.

Original publication

DOI

10.1084/jem.20161827

Type

Journal article

Journal

J Exp Med

Publication Date

02/10/2017

Volume

214

Pages

3085 - 3104

Keywords

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