SATB1 packages densely looped, transcriptionally active chromatin for coordinated expression of cytokine genes

Abstract

email terumiks@lbl.gov 2 SUMMARY SATB1 is an important regulator of nuclear architecture that anchors specialized DNA sequences onto its cage-like network and recruits chromatin remodeling/modifying factors to control gene transcription. We studied the role of SATB1 in regulating the coordinated expression of Il5, Il4, and Il13 from the 200kb cytokine gene cluster region of mouse chromosome 11 during T-helper 2 (Th2)-cell activation. We show that upon cell activation, SATB1 is rapidly induced to form a unique transcriptionally-active chromatin structure that includes the cytokine gene region.Chromatin is folded into numerous small loops all anchored by SATB1, is histone H3 acetylated at lysine 9/14, and associated with Th2-specific factors, GATA3, STAT6, c-Maf, the chromatinremodeling enzyme Brg-1, and RNA polymerase II across the 200kb region. Before activation, the chromatin displays some of these features, such as association with GATA3 and STAT6, but these were insufficient for cytokine gene expression. Using RNA interference (RNAi), we show that upon cell activation, SATB1 is not only required for chromatin folding into dense loops, but also for c-Maf induction and subsequently for Il4, Il5, and Il13 transcription. Our results show that SATB1 is an important determinant for chromatin architecture that constitutes a novel higher-order, transcriptionally-active chromatin structure upon Th2-cell activation.

GATA simple sequence repeats function as enhancer blocker boundaries

“…Presence of many SSR-binding proteins [29][30][31] further strengthens the view that these repeats may have functional relevance. One of the major SSRs in vertebrates, the GATA tetranucleotide, has many unique features such as preferred higher occurrence of (GATA) [10][11][12] , greater abundance on the mammalian Y chromosome and close association with developmentally regulated genes 9,10 . We here show that these GATA elements function as enhancer blocker elements that can demarcate functional domains in the genome.…”

“…We also noticed a frequent association of matrix attachment region (MAR) potential sequences with the GATA repeats 10 . MAR DNA, by its association to the nuclear matrix, creates chromatin domains that are topologically constrained, which helps in regulating genes and organizing the genome in eukaryotes [11][12][13][14][15] . These observations suggested a gene regulation and genome packaging-related function for this SSR element.…”

“…GATA repeat elements (GEs), which are highly abundant on the sex chromosomes of several organisms, have GATA [10][11][12] as the most abundant size of this repeat and are present almost exclusively in the intergenic regions 10 . GATA repeats have also been found to be associated with genes that are expressed early during development while the GE-devoid region of Y chromosome contains genes that are expressed late during spermatogenesis.…”

The role of nuclear organization in cancer

“…During T cell development, SATB1 plays a major role in gene expression by acting as a docking platform to recruit activators and repressors [60,61]. Its function as either activator or repressor depends on specific post-translational modifications of the protein [62].…”

Enforced Expression of Gata3 in T Cells and Group 2 Innate Lymphoid Cells Increases Susceptibility to Allergic Airway Inflammation in Mice

“…A suggested mechanism for this activity is that Gata3 causes chromatin remodeling in the Th2 cytokine locus, in conjunction with various other transcriptional regulators including c-maf, Irf4, SatB1, and Ctcf (12,15,16). Apart from its function in Th cells, Gata3 is also essential for early stages of T cell development in the thymus (12,17).…”