National Centre for Cell Science, Ganeshkhind, Pune, India.
PLoS Biol. 2010 Jan 26;8(1):e1000296. doi: 10.1371/journal.pbio.1000296.
In vertebrates, the conserved Wnt signalling cascade promotes the stabilization and nuclear accumulation of beta-catenin, which then associates with the lymphoid enhancer factor/T cell factor proteins (LEF/TCFs) to activate target genes. Wnt/beta -catenin signalling is essential for T cell development and differentiation. Here we show that special AT-rich binding protein 1 (SATB1), the T lineage-enriched chromatin organizer and global regulator, interacts with beta-catenin and recruits it to SATB1's genomic binding sites. Gene expression profiling revealed that the genes repressed by SATB1 are upregulated upon Wnt signalling. Competition between SATB1 and TCF affects the transcription of TCF-regulated genes upon beta-catenin signalling. GATA-3 is a T helper type 2 (T(H)2) specific transcription factor that regulates production of T(H)2 cytokines and functions as T(H)2 lineage determinant. SATB1 positively regulated GATA-3 and siRNA-mediated knockdown of SATB1 downregulated GATA-3 expression in differentiating human CD4(+) T cells, suggesting that SATB1 influences T(H)2 lineage commitment by reprogramming gene expression. In the presence of Dickkopf 1 (Dkk1), an inhibitor of Wnt signalling, GATA-3 is downregulated and the expression of signature T(H)2 cytokines such as IL-4, IL-10, and IL-13 is reduced, indicating that Wnt signalling is essential for T(H)2 differentiation. Knockdown of beta-catenin also produced similar results, confirming the role of Wnt/beta-catenin signalling in T(H)2 differentiation. Furthermore, chromatin immunoprecipitation analysis revealed that SATB1 recruits beta-catenin and p300 acetyltransferase on GATA-3 promoter in differentiating T(H)2 cells in a Wnt-dependent manner. SATB1 coordinates T(H)2 lineage commitment by reprogramming gene expression. The SATB1:beta-catenin complex activates a number of SATB1 regulated genes, and hence this study has potential to find novel Wnt responsive genes. These results demonstrate that SATB1 orchestrates T(H)2 lineage commitment by mediating Wnt/beta-catenin signalling. This report identifies a new global transcription factor involved in beta-catenin signalling that may play a major role in dictating the functional outcomes of this signalling pathway during development, differentiation, and tumorigenesis.
在脊椎动物中，保守的 Wnt 信号级联反应促进β-连环蛋白的稳定和核积累，然后β-连环蛋白与淋巴增强因子/ T 细胞因子蛋白（LEF/TCFs）结合，激活靶基因。Wnt/β-连环蛋白信号对于 T 细胞的发育和分化是必不可少的。在这里，我们表明，富含特殊 AT 的结合蛋白 1（SATB1），即 T 系特异性染色质组织者和全局调节剂，与β-连环蛋白相互作用，并将其募集到 SATB1 的基因组结合位点。基因表达谱分析显示，SATB1 抑制的基因在 Wnt 信号作用下上调。SATB1 和 TCF 之间的竞争会影响β-连环蛋白信号作用下 TCF 调节基因的转录。GATA-3 是 T 辅助型 2（T(H)2）特异性转录因子，调节 T(H)2 细胞因子的产生，并作为 T(H)2 谱系决定因子发挥作用。SATB1 正向调节 GATA-3，siRNA 介导的 SATB1 敲低下调分化的人 CD4+T 细胞中的 GATA-3 表达，表明 SATB1 通过重新编程基因表达来影响 T(H)2 谱系决定。在 Dickkopf 1（Dkk1）存在的情况下，Wnt 信号的抑制剂，GATA-3 下调，IL-4、IL-10 和 IL-13 等特征性 T(H)2 细胞因子的表达减少，表明 Wnt 信号对于 T(H)2 分化是必不可少的。β-连环蛋白的敲低也产生了类似的结果，证实了 Wnt/β-连环蛋白信号在 T(H)2 分化中的作用。此外，染色质免疫沉淀分析显示，SATB1 在 Wnt 依赖的方式下募集β-连环蛋白和 p300 乙酰转移酶到分化的 T(H)2 细胞中的 GATA-3 启动子上。SATB1 通过重新编程基因表达来协调 T(H)2 谱系决定。SATB1：β-连环蛋白复合物激活了许多 SATB1 调节的基因，因此本研究有可能发现新的 Wnt 反应基因。这些结果表明，SATB1 通过介导 Wnt/β-连环蛋白信号来协调 T(H)2 谱系决定。本报告确定了一种新的参与β-连环蛋白信号的全局转录因子，它可能在决定该信号通路在发育、分化和肿瘤发生过程中的功能结果方面发挥主要作用。
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