Loughran, SJ;
Comoglio, F;
Hamey, FK;
Giustacchini, A;
Errami, Y;
Earp, E;
Gottgens, B;
... Green, AR; + view all
(2017)
Mbd3/NuRD controls lymphoid cell fate and inhibits tumorigenesis by repressing a B cell transcriptional program.
Journal of Experimental Medicine
, 214
(10)
pp. 3085-3104.
10.1084/jem.20161827.
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Abstract
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.
Type: | Article |
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Title: | Mbd3/NuRD controls lymphoid cell fate and inhibits tumorigenesis by repressing a B cell transcriptional program |
Open access status: | An open access version is available from UCL Discovery |
DOI: | 10.1084/jem.20161827 |
Publisher version: | http://doi.org/10.1084/jem.20161827 |
Language: | English |
Additional information: | © 2017 Loughran et al. This article is distributed under the terms of an Attribution–Noncommercial–Share Alike–No Mirror Sites license for the first six months after the publication date (see http://www.rupress.org /terms/). After six months it is available under a Creative Commons License (Attribution–Noncommercial– Share Alike 4.0 International license, as described at https://creativecommons.org/licenses/by-nc-sa/4.0/). |
Keywords: | Science & Technology, Life Sciences & Biomedicine, Immunology, Medicine, Research & Experimental, Research & Experimental Medicine, CHROMATIN REMODELER MI-2-BETA, GENE-EXPRESSION ANALYSIS, EMBRYONIC STEM-CELLS, DIFFUSION MAPS, HEMATOPOIETIC PROGENITORS, ENHANCER REPERTOIRES, LINEAGE COMMITMENT, PLURIPOTENT CELLS, BONE-MARROW, NURD |
UCL classification: | UCL UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Population Health Sciences > UCL GOS Institute of Child Health UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Population Health Sciences > UCL GOS Institute of Child Health > Infection, Immunity and Inflammation Dept |
URI: | https://discovery.ucl.ac.uk/id/eprint/10039553 |
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