Abstract
Regulatory T cells (T(reg) cells) are essential for self-tolerance and immune homeostasis. Lack of effector T cell (T(eff) cell) function and gain of suppressive activity by T(reg) cells are dependent on the transcriptional program induced by Foxp3. Here we report that repression of SATB1, a genome organizer that regulates chromatin structure and gene expression, was crucial for the phenotype and function of T(reg) cells. Foxp3, acting as a transcriptional repressor, directly suppressed the SATB1 locus and indirectly suppressed it through the induction of microRNAs that bound the SATB1 3' untranslated region. Release of SATB1 from the control of Foxp3 in T(reg) cells caused loss of suppressive function, establishment of transcriptional T(eff) cell programs and induction of T(eff) cell cytokines. Our data support the proposal that inhibition of SATB1-mediated modulation of global chromatin remodeling is pivotal for maintaining T(reg) cell functionality.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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3' Untranslated Regions / genetics
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3' Untranslated Regions / immunology
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Animals
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Cell Differentiation / drug effects
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Chromatin Assembly and Disassembly / drug effects
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Chromatin Assembly and Disassembly / immunology*
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Flow Cytometry
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Forkhead Transcription Factors / genetics
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Forkhead Transcription Factors / immunology*
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Forkhead Transcription Factors / metabolism
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Gene Expression Profiling
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Gene Expression Regulation*
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Genome, Human
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Genome-Wide Association Study
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Humans
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Lentivirus
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Lymphocyte Activation / drug effects
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Matrix Attachment Region Binding Proteins / genetics
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Matrix Attachment Region Binding Proteins / immunology*
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Matrix Attachment Region Binding Proteins / metabolism
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Mice
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Mice, Inbred C57BL
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Mice, Knockout
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MicroRNAs / immunology
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MicroRNAs / metabolism
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MicroRNAs / pharmacology
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RNA Interference
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RNA, Small Interfering / immunology
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RNA, Small Interfering / metabolism
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RNA, Small Interfering / pharmacology
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Reverse Transcriptase Polymerase Chain Reaction
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Self Tolerance* / drug effects
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Self Tolerance* / genetics
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Self Tolerance* / immunology
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T-Lymphocytes, Regulatory / cytology
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T-Lymphocytes, Regulatory / immunology*
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T-Lymphocytes, Regulatory / metabolism
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Transduction, Genetic
Substances
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3' Untranslated Regions
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FOXP3 protein, human
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Forkhead Transcription Factors
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Matrix Attachment Region Binding Proteins
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MicroRNAs
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RNA, Small Interfering
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SATB1 protein, human
Associated data
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GEO/GSE15390
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GEO/GSE20995