title: Harnessing of the nucleosome-remodeling-deacetylase complex controls lymphocyte development and prevents leukemogenesis.
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.
authors.affiliation: FAS Research Computing, Harvard University, Cambridge, MA 02138, USA.
authors.forename: Jiangwen
authors.initials: J
authors.lastname: Zhang
authors.affiliation: CBRC, Mass General Hospital, Harvard Medical School, Charlestown, MA, 02129, USA.
authors.forename: Audrey F
authors.initials: AF
authors.lastname: Jackson
authors.affiliation: CBRC, Mass General Hospital, Harvard Medical School, Charlestown, MA, 02129, USA.
authors.forename: Taku
authors.initials: T
authors.lastname: Naito
authors.affiliation: Department of Medicine, The University of Chicago, Chicago, IL 60637, USA.
authors.forename: Marei
authors.initials: M
authors.lastname: Dose
authors.affiliation: CBRC, Mass General Hospital, Harvard Medical School, Charlestown, MA, 02129, USA.
authors.forename: John
authors.initials: J
authors.lastname: Seavitt
authors.affiliation: CBRC, Mass General Hospital, Harvard Medical School, Charlestown, MA, 02129, USA.
authors.forename: Feifei
authors.initials: F
authors.lastname: Liu
authors.affiliation: CBRC, Mass General Hospital, Harvard Medical School, Charlestown, MA, 02129, USA.
authors.forename: Elizabeth J
authors.initials: EJ
authors.lastname: Heller
authors.affiliation: CBRC, Mass General Hospital, Harvard Medical School, Charlestown, MA, 02129, USA.
authors.forename: Mariko
authors.initials: M
authors.lastname: Kashiwagi
authors.affiliation: CBRC, Mass General Hospital, Harvard Medical School, Charlestown, MA, 02129, USA.
authors.forename: Toshimi
authors.initials: T
authors.lastname: Yoshida
authors.affiliation: Department of Medicine, The University of Chicago, Chicago, IL 60637, USA.
authors.forename: Fotini
authors.initials: F
authors.lastname: Gounari
authors.affiliation: Department of Cancer Biology, The Scripps Research Institute, Jupiter, FL 33458, USA.
authors.forename: Howard T
authors.initials: HT
authors.lastname: Petrie
authors.affiliation: CBRC, Mass General Hospital, Harvard Medical School, Charlestown, MA, 02129, USA.
authors.forename: Katia
authors.initials: K
authors.lastname: Georgopoulos
mesh_terms: D000818:Animals; D001483:Base Sequence; D002454:Cell Differentiation / Q000235:genetics; D042002:Chromatin Assembly and Disassembly; D020869:Gene Expression Profiling; D053263:Gene Regulatory Networks; D051740:Ikaros Transcription Factor / Q000235:genetics / Q000378:metabolism; D007938:Leukemia / Q000235:genetics; D008214:Lymphocytes / Q000201:enzymology* / Q000276:immunology; D056245:Mi-2 Nucleosome Remodeling and Deacetylase Complex / Q000378:metabolism*; D051379:Mice; D059372:Nucleotide Motifs; D011485:Protein Binding; D060168:Thymocytes / Q000378:metabolism
chemical_list: D051740:Ikaros Transcription Factor; D056245:Mi-2 Nucleosome Remodeling and Deacetylase Complex
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