Abstract
Changes in chromatin structure underlie the activation or silencing of genes during development. The chromatin remodeler Mi-2beta is highly expressed in thymocytes and is presumed to be a transcriptional repressor because of its presence in the nucleosome remodeling deacetylase (NuRD) complex. Using conditional inactivation, we show that Mi-2beta is required at several steps during T cell development: for differentiation of beta selected immature thymocytes, for developmental expression of CD4, and for cell divisions in mature T cells. We further show that Mi-2beta plays a direct role in promoting CD4 gene expression. Mi-2beta associates with the CD4 enhancer as well as the E box binding protein HEB and the histone acetyltransferase (HAT) p300, enabling their recruitment to the CD4 enhancer and causing histone H3-hyperacetylation to this regulatory region. These findings provide important insights into the regulation of CD4 expression during T cell development and define a role for Mi-2beta in gene activation.
Publication types
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Acetyltransferases / metabolism
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Animals
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Apoptosis
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Basic Helix-Loop-Helix Transcription Factors
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CD4 Antigens / biosynthesis*
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CD4 Antigens / genetics*
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CD4 Antigens / immunology
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CD4 Antigens / metabolism
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Cell Cycle Proteins / metabolism
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Cell Differentiation
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Cell Division
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Cells, Cultured
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Chromatin Assembly and Disassembly*
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DNA-Binding Proteins / metabolism
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Enhancer Elements, Genetic / genetics
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Flow Cytometry
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Gene Expression Regulation*
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Histone Acetyltransferases
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Histone Deacetylases / metabolism
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Mi-2 Nucleosome Remodeling and Deacetylase Complex
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Mice
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Mice, Transgenic
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Receptors, Antigen, T-Cell / immunology
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Receptors, Antigen, T-Cell / metabolism
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T-Lymphocytes / cytology*
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T-Lymphocytes / immunology
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T-Lymphocytes / metabolism*
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Thymus Gland / cytology
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Thymus Gland / immunology
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Thymus Gland / metabolism
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Transcription Factors / metabolism
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Transcriptional Activation
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Transgenes / genetics
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p300-CBP Transcription Factors
Substances
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Basic Helix-Loop-Helix Transcription Factors
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CD4 Antigens
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Cell Cycle Proteins
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DNA-Binding Proteins
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Receptors, Antigen, T-Cell
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Tcf12 protein, mouse
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Transcription Factors
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Acetyltransferases
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Histone Acetyltransferases
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p300-CBP Transcription Factors
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p300-CBP-associated factor
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Histone Deacetylases
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Mi-2 Nucleosome Remodeling and Deacetylase Complex