1. Repression of the genome organizer SATB1 in regulatory T cells is required for suppressive function and inhibition of effector differentiation.
- Author
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Beyer M, Thabet Y, Müller RU, Sadlon T, Classen S, Lahl K, Basu S, Zhou X, Bailey-Bucktrout SL, Krebs W, Schönfeld EA, Böttcher J, Golovina T, Mayer CT, Hofmann A, Sommer D, Debey-Pascher S, Endl E, Limmer A, Hippen KL, Blazar BR, Balderas R, Quast T, Waha A, Mayer G, Famulok M, Knolle PA, Wickenhauser C, Kolanus W, Schermer B, Bluestone JA, Barry SC, Sparwasser T, Riley JL, and Schultze JL
- Subjects
- 3' Untranslated Regions genetics, 3' Untranslated Regions immunology, Animals, Cell Differentiation drug effects, Chromatin Assembly and Disassembly drug effects, Flow Cytometry, Forkhead Transcription Factors genetics, Forkhead Transcription Factors metabolism, Gene Expression Profiling, Genome, Human, Genome-Wide Association Study, Humans, Lentivirus, Lymphocyte Activation drug effects, Matrix Attachment Region Binding Proteins genetics, Matrix Attachment Region Binding Proteins metabolism, Mice, Mice, Inbred C57BL, Mice, Knockout, MicroRNAs immunology, MicroRNAs metabolism, MicroRNAs pharmacology, RNA Interference, RNA, Small Interfering immunology, RNA, Small Interfering metabolism, RNA, Small Interfering pharmacology, Reverse Transcriptase Polymerase Chain Reaction, T-Lymphocytes, Regulatory cytology, T-Lymphocytes, Regulatory metabolism, Transduction, Genetic, Chromatin Assembly and Disassembly immunology, Forkhead Transcription Factors immunology, Gene Expression Regulation, Matrix Attachment Region Binding Proteins immunology, Self Tolerance drug effects, Self Tolerance genetics, Self Tolerance immunology, T-Lymphocytes, Regulatory immunology
- 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.
- Published
- 2011
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