1. Harnessing of the nucleosome-remodeling-deacetylase complex controls lymphocyte development and prevents leukemogenesis.
- Author
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Zhang J, Jackson AF, Naito T, Dose M, Seavitt J, Liu F, Heller EJ, Kashiwagi M, Yoshida T, Gounari F, Petrie HT, and Georgopoulos K
- Subjects
- Animals, Base Sequence, Cell Differentiation genetics, Chromatin Assembly and Disassembly, Gene Expression Profiling, Gene Regulatory Networks, Ikaros Transcription Factor genetics, Ikaros Transcription Factor metabolism, Leukemia genetics, Lymphocytes immunology, Mice, Nucleotide Motifs, Protein Binding, Thymocytes metabolism, Lymphocytes enzymology, Mi-2 Nucleosome Remodeling and Deacetylase Complex metabolism
- 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.
- Published
- 2011
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