Acetylation-Dependent Interaction of SATB1 and CtBP1 Mediates Transcriptional Repression by SATB1

Abstract

Special AT-rich binding protein 1 (SATB1) acts as a global regulator of gene expression by recruiting various corepressor or coactivator complexes, thereby establishing a unique chromatin structure at its genomic targets in a context-dependent manner. Although SATB1 acts predominantly as a repressor via recruitment of histone deacetylase 1 (HDAC1) complexes, the precise mechanism of global repression is not clear. Here we report that SATB1 and C-terminal binding protein 1 (CtBP1) form a repressor complex in vivo. The interaction occurs via the CtBP1 interaction consensus motif PVPLS within the PDZ-like domain of SATB1. The acetylation of SATB1 upon LiCl and ionomycin treatments disrupts its association with CtBP1, resulting in enhanced target gene expression. Chromatin immunoprecipitation analysis indicated that the occupancy of CtBP1 and HDAC1 is gradually decreased and the occupancy of PCAF is elevated at the SATB1 binding sites within the human interleukin-2 and mouse c-Myc promoters. Moreover, gene expression profiling studies using cells in which expression of SATB1 and CtBP1 was silenced indicated commonly targeted genes that may be coordinately repressed by the SATB1-CtBP1 complex. Collectively, these results provide a mechanistic insight into the role of SATB1-CtBP1 interaction in the repression and derepression of SATB1 target genes during Wnt signaling in T cells.The T-cell-enriched transcription factor special AT-rich binding protein 1 (SATB1) regulates the spatiotemporal expression of a large number of genes involved in T-cell development (1). SATB1 participates in the maintenance of chromatin architecture in a cell-type-specific manner by organizing higher-order chromatin loops into distinct domains via periodic anchoring of non-base-pairing regions to the nuclear matrix (9, 10, 25). In primary thymocytes, SATB1 exhibits a cagelike network distribution circumscribing heterochromatin domains and regulates distant genes in a coordinated manner (10). Implications of SATB1 domains in its functional regulation impart unique properties to this chromatin organizer. The C-terminal homeodomain (HD) acts in concert with the Cut repeat-containing domain (CD) and directs high-affinity binding of SATB1 to its targets in a sequence-specific manner (35). The N-terminal PDZ-like domain aids in the formation of a homodimer that is essential for the DNA binding activity of SATB1 (15,35). The N-terminal region harboring the PDZlike domain is a putative interface for its interaction with various cellular and viral proteins (25-27). SATB1 regulates gene expression in two distinct modes. Primary regulation is by specific binding of SATB1 to promoters and upstream regions, thereby directly influencing the promoter activity. SATB1 is known to directly regulate a number of genes, including those encoding globin, interleukin-2 (IL-2), and IL-2 receptor ␣ (IL-2R␣), by recruiting either CBP (48) or histone deacetylase 1 (HDAC1) (26,27). Secondly, context-specific regulation of SATB1 stems from its unique ability to bind to mat...

Expression and significance of SATB1 in the development of breast cancer

“…The mechanism of increased SATB1, the signaling pathway involved in the development of the tumor, and the role of this protein in regulating signal transductions have not been thoroughly examined. Some studies reported that Foxp3 microRNAs can regulate the SATB1 expression level (Beyer et al, 2011;Li et al, 2011;Lena et al, 2012;McInnes et al, 2012;Yang et al, 2012), and some post-translational modifications with biological significance have been identified (Pavan Kumar et al, 2006;Purbey et al, 2009). Another study found that the ataxia telangiectasia mutated protein can inhibit SATB1-induced malignant progression of mammary epithelial cells .…”

Satb1 and Satb2 regulate embryonic stem cell differentiation and Nanog expression

“…Satb1 and Satb2 can form both homodimers and heterodimers via a highly conserved PDZ domain (Galande et al 2001;T Treiber and R Grosschedl, unpubl.). Interestingly, the PDZ domain of Satb1, but not that of Satb2, harbors a short peptide sequence that mediates association with the corepressor CtBP1 (C-terminal binding protein 1) (Purbey et al 2009). In addition, Satb2 contains two SUMO acceptor sites that are not present in Satb1 (Dobreva et al 2003).…”

“…À/À cells, we performed ChIP experiments with antibodies against SNF2H, PCAF, CTBP1, and HDAC1, which have been reported to bind Satb1 (Yasui et al 2002;Kumar et al 2005;Pavan Kumar et al 2006;Purbey et al 2009). In Satb1 À/À cells, we detected a modest increase of SNF2H at the Nanog, Klf4, and Bcl2 promoters (Fig.…”

Phosphorylation-Dependent Interaction of SATB1 and PIAS1 Directs SUMO-Regulated Caspase Cleavage of SATB1

“…Previously it was suggested that the N terminus of SATB1 facilitates SATB1 homodimerization and interaction with sumoylated PML and PML NBs, in addition to association with a number of transcription factors (26,46,48,49). Homodimerization of SATB1 is supposedly critical for SATB1 to localize to MAR elements.…”