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| Title | Global Regulator SATB1 Recruits β-Catenin and Regulates TH2 Differentiation in Wnt-Dependent Manner |
| Author/s |
Dimple Notani, Kamalvishnu P. Gottimukkala,
Ranveer S. Jayani, Amita S. Limaye,
Madhujit V. Damle
National Centre for Cell Science, Savitribai Phule Pune University Campus, Pune 411 007 India Sameet Mehta Centre for Modeling and Simulation, Savitribai Phule Pune University, Pune 411 007 India Prabhat Kumar Purbey, Jomon Joseph, and Sanjeev Galande National Centre for Cell Science, Savitribai Phule Pune University Campus, Pune 411 007 India |
| Abstract | In vertebrates, the conserved Wnt signalling cascade promotes the stabilization and nuclear accumulation of β-catenin, which then associates with the lymphoid enhancer factor/T cell factor proteins (LEF/TCFs) to activate target genes. Wnt/β-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 β-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 β-catenin signalling. GATA-3 is a T helper type 2 (TH2) specific transcription factor that regulates production of TH2 cytokines and functions as TH2 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 TH2 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 TH2 cytokines such as IL-4, IL-10, and IL-13 is reduced, indicating that Wnt signalling is essential for TH2 differentiation. Knockdown of β-catenin also produced similar results, confirming the role of Wnt/β-catenin signalling in TH2 differentiation. Furthermore, chromatin immunoprecipitation analysis revealed that SATB1 recruits β-catenin and p300 acetyltransferase on GATA-3 promoter in differentiating TH2 cells in a Wnt-dependent manner. SATB1 coordinates TH2 lineage commitment by reprogramming gene expression. The SATB1:β-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 TH2 lineage commitment by mediating Wnt/β-catenin signalling. This report identifies a new global transcription factor involved in β-catenin signalling that may play a major role in dictating the functional outcomes of this signalling pathway during development, differentiation, and tumorigenesis. |
| Keywords | |
| Download | [1.4M pdf] |
| Citing This Document | Dimple Notani, Kamalvishnu P. Gottimukkala, Ranveer S. Jayani, Amita S. Limaye, Madhujit V. Damle, Sameet Mehta, Prabhat Kumar Purbey, Jomon Joseph, and Sanjeev Galande , Global Regulator SATB1 Recruits β-Catenin and Regulates TH2 Differentiation in Wnt-Dependent Manner . Technical Report CMS-TR-20100114 of the Centre for Modeling and Simulation, Savitribai Phule Pune University, Pune 411007, India (2010); available at http://cms.unipune.ac.in/reports/. |
| Notes, Published Reference, Etc. | Published as PLoS Biology 8(1) e1000296 (2010) |
| Contact | sameet AT cms.unipune.ac.in |
| Supplementary Material |