Global Regulator SATB1 Recruits β-Catenin and Regulates TH2 Differentiation in Wnt-Dependent Manner

Ranveer S Jayani,Amita S Limaye,Madhujit V Damle,Sanjeev Galande,Sameet Mehta,Prabhat Kumar Purbey,Dimple Notani,Kamalvishnu P Gottimukkala,Jomon Joseph,Roel Nusse

doi:10.1371/journal.pbio.1000296

Ranveer S Jayani, Amita S Limaye + Show 8 more

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https://doi.org/10.1371/journal.pbio.1000296

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Abstract

Author SummaryIn vertebrates the canonical Wnt signalling culminates in β-catenin moving into the nucleus where it activates transcription of target genes. Wnt/β-catenin signalling is essential for the thymic maturation and differentiation of naïve T cells. Here we show that SATB1, a T cell lineage-enriched chromatin organizer and global regulator, binds to β-catenin and recruits it to SATB1's genomic binding sites so that genes formerly repressed by SATB1 are upregulated by Wnt signalling. Some of the genes known to be regulated by SATB1 (such as genes encoding cytokines and the transcription factor GATA3) are required for differentiation of Th2 cells, an important subset of helper T cells. Specifically we show that siRNA-mediated knockdown of SATB1 downregulated GATA-3 expression in differentiating human CD4+ T cells. Inhibiting Wnt signalling led to downregulation of GATA-3 and of signature TH2 cytokines such as IL-4, IL-10, and IL-13. Knockdown of β-catenin also produced similar results, thus together these data confirm the role of Wnt/β-catenin signalling in TH2 differentiation. Our data demonstrate that SATB1 orchestrates TH2 lineage commitment by modulating Wnt/β-catenin signalling.

Highlights

Wingless type (Wnt) growth factors regulate a variety of developmental processes by altering specific gene expression patterns [1]
We show that special AT-rich binding protein 1 (SATB1), a T cell lineageenriched chromatin organizer and global regulator, binds to b-catenin and recruits it to SATB1’s genomic binding sites so that genes formerly repressed by SATB1 are upregulated by Wnt signalling
Some of the genes known to be regulated by SATB1 are required for differentiation of Th2 cells, an important subset of helper T cells

Summary

Introduction

Wnt growth factors regulate a variety of developmental processes by altering specific gene expression patterns [1]. Binding of Wnt to Fz (Table S1) elicits a complex cascade of molecular events culminating in the inhibition of the negative regulatory kinase GSK-3b [3]. Dephosphorylated b-catenin accumulates inside the nucleus [5] where it associates with the lymphoid enhancer factor/T cell factor (LEF/TCF) transcription factors to induce target gene transcription [6]. The C-terminus of b-catenin is indispensable for the transactivation function, presumably since it harbours binding sites for transcriptional coactivators such as p300/CBP and TBP [7,8]. Recruitment of chromatin remodelling factors on TCF’s genomic targets to modulate the gene transcription appears to be the principal function of stabilized b-catenin [8]

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