Abstract
SATB1 (special AT-rich sequence binding protein 1) organizes cell
type-specific nuclear architecture by anchoring specialized DNA sequences
and recruiting chromatin remodeling factors to control gene transcription.
We studied the role of SATB1 in regulating the coordinated expression
of Il5, Il4 and Il13, located in the 200-kb T-helper 2 (T(H)2) cytokine
locus on mouse chromosome 11. We show that on T(H)2 cell activation,
SATB1 expression is rapidly induced to form a unique transcriptionally
active chromatin structure at the cytokine locus. In this structure,
chromatin is folded into numerous small loops, all anchored to SATB1
at their base. In addition, histone H3 is acetylated at Lys9 and
Lys14, and the T(H)2-specific factors GATA3, STAT6 and c-Maf, the
chromatin-remodeling enzyme Brg1 and RNA polymerase II are all bound
across the 200-kb region. Before activation, the T(H)2 cytokine locus
is already associated with GATA3 and STAT6, showing some looping,
but these are insufficient to induce cytokine gene expression. Using
RNA interference, we show that on cell activation, SATB1 is required
not only for compacting chromatin into dense loops at the 200-kb
cytokine locus but also for inducing Il4, Il5, Il13 and c-Maf expression.
Thus, SATB1 is a necessary determinant for the hitherto unidentified
higher-order, transcriptionally active chromatin structure that forms
on T(H)2 cell activation.
- acetylation
- animals
- binding_sites
- chromatin,_chemistry/metabolism
- chromatin_immunoprecipitation,_methods
- chromosomes,_chemistry
- cytokines,_metabolism
- dna-binding_proteins,_genetics/physiology
- dna_helicases,_metabolism
- dna_repair_enzymes,_genetics
- gata3_transcription_factor,_metabolism
- gene_expression_regulation
- histones,_metabolism
- histone_acetyltransferases,_metabolism
- locus_control_region
- lymphocyte_activation,_physiology
- matrix_attachment_region_binding_proteins,_physiology
- mice
- mice,_inbred_akr
- models,_biological
- nuclear_proteins,_metabolism
- nucleic_acid_conformation
- promoter_regions_(genetics)
- proto-oncogene_proteins_c-maf,_metabolism
- rna_polymerase_ii,_metabolism
- stat6_transcription_factor,_metabolism
- th2_cells,_metabolism
- transcription,_genetic,_physiology
- transcription_factors,_metabolism
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