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Harnessing of the nucleosome-remodeling-deacetylase complex controls lymphocyte development and prevents leukemogenesis

Nature Immunology volume 13, pages 86–94 (2012)Cite this article

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Abstract

Cell fate depends on the interplay between chromatin regulators and transcription factors. Here we show that activity of the Mi-2β nucleosome-remodeling and histone-deacetylase (NuRD) complex was controlled by the Ikaros family of lymphoid lineage–determining proteins. Ikaros, an integral component of the NuRD complex in lymphocytes, tethered this complex to active genes encoding molecules involved in lymphoid differentiation. Loss of Ikaros DNA-binding activity caused a local increase in chromatin remodeling and histone deacetylation and suppression of lymphoid cell–specific gene expression. Without Ikaros, the NuRD complex also redistributed to transcriptionally poised genes that were not targets of Ikaros (encoding molecules involved in proliferation and metabolism), which induced their reactivation. Thus, release of NuRD from Ikaros regulation blocks lymphocyte maturation and mediates progression to a leukemic state by engaging functionally opposing epigenetic and genetic networks.

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Figure 1: Composition of the NuRD complex in primary DP thymocytes.
Figure 2: Genome-wide mapping of the Ikaros-NuRD complex in permissive chromatin and transcriptionally active genes.
Figure 3: Loss of Ikaros results in a gain in enrichment for Mi-2β in chromatin and chromatin remodeling, and histone deacetylation by Mi-2β.
Figure 4: Targeting of the Mi-2β–NuRD complex to a lymphoid cell–specific gene network.
Figure 5: Gene-ontology pathway analysis of gene targets of Mi-2β.
Figure 6: Loss of Ikaros-mediated effects on gene expression demonstrates two functionally opposite mechanisms of NuRD-dependent transcriptional regulation.

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Acknowledgements

We thank P. Gomez for analysis of the expression of Mi-2β protein in thymocytes; the Kingston laboratory (Massachusetts General Hospital) for the hSWI-SNF complex and help with setting up the mononucleosome and 5S array assays; I. Joshi for help with cell sorting; B. Czyzewski for mouse husbandry; and B. Morgan for discussions of the project and critical review of the manuscript. Protein microsequencing was done at the Microchemistry and Proteomics Facility of Harvard University, Cambridge, and at the Taplin Mass Spectrometry Facility of Harvard Medical School, Boston, and high-throughput DNA sequencing and RNA profiling were done at the Bauer Center for Genomic Research of Harvard University, Cambridge. Supported by the US National Institutes of Health (2T32AI007529 to A.F.J.; and 5R01AI042254 and R01CA158006 to K.G.).

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Author notes

  1. Taku Naito

    Present address: Present address: RIKEN Research Center for Allergy and Immunology, Kanagawa, Japan.,

  2. Jiangwen Zhang, Audrey F Jackson and Taku Naito: These authors contributed equally to this work.

Authors and Affiliations

  1. Faculty of Arts and Sciences Research Computing, Harvard University, Cambridge, Massachusetts, USA

    Jiangwen Zhang

  2. Cuteneous Biology Research Center, Massachusetts General Hospital, Harvard Medical School, Charlestown, Massachusetts, USA

    Audrey F Jackson, Taku Naito, John Seavitt, Feifei Liu, Elizabeth J Heller, Mariko Kashiwagi, Toshimi Yoshida & Katia Georgopoulos

  3. Department of Medicine, The University of Chicago, Chicago, Illinois, USA

    Marei Dose & Fotini Gounari

  4. Department of Cancer Biology, The Scripps Research Institute, Jupiter, Florida, USA

    Howard T Petrie

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Contributions

J.Z., A.F.J., T.N., M.D., E.J.H., J.S., F.L., M.K. and T.Y. designed and did experiments and analyzed experimental data; H.T.P. designed expression studies of wild-type thymocyte subsets and provided data for analysis; F.G. and K.G. supervised research and analyzed data; and J.Z. and K.G. wrote the manuscript.

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Correspondence to Katia Georgopoulos.

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Zhang, J., Jackson, A., Naito, T. et al. Harnessing of the nucleosome-remodeling-deacetylase complex controls lymphocyte development and prevents leukemogenesis. Nat Immunol 13, 86–94 (2012). https://doi.org/10.1038/ni.2150

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