Developmental Cell
Volume 21, Issue 3, 13 September 2011, Pages 559-574
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Article
A Wt1-Controlled Chromatin Switching Mechanism Underpins Tissue-Specific Wnt4 Activation and Repression

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Summary

Wt1 regulates the epithelial-mesenchymal transition (EMT) in the epicardium and the reverse process (MET) in kidney mesenchyme. The mechanisms underlying these reciprocal functions are unknown. Here, we show in both embryos and cultured cells that Wt1 regulates Wnt4 expression dichotomously. In kidney cells, Wt1 recruits Cbp and p300 as coactivators; in epicardial cells it enlists Basp1 as a corepressor. Surprisingly, in both tissues, Wt1 loss reciprocally switches the chromatin architecture of the entire Ctcf-bounded Wnt4 locus, but not the flanking regions; we term this mode of action “chromatin flip-flop.” Ctcf and cohesin are dispensable for Wt1-mediated chromatin flip-flop but essential for maintaining the insulating boundaries. This work demonstrates that a developmental regulator coordinates chromatin boundaries with the transcriptional competence of the flanked region. These findings also have implications for hierarchical transcriptional regulation in development and disease.

Highlights

► Wt1 is essential for Wnt4 expression and nephron formation ► Wt1 activates Wnt4 expression in the kidney while repressing it in the epicardium ► Wt1 controls Wnt4 dichotomously via a mechanism we term chromatin flip-flop ► CTCF/cohesin maintain Wnt4 locus insulation but are dispensable for the flip-flop

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