A Wt1-Controlled Chromatin Switching Mechanism Underpins Tissue-Specific Wnt4 Activation and Repression

Abdelkader Essafi, Anna Webb, Rachel L Berry, Joan Slight, Sally F Burn, Lee Spraggon, Victor Velecela, Ofelia M Martinez-Estrada, John H Wiltshire, Stefan G E Roberts, David Brownstein, Jamie A Davies, Nicholas D Hastie, Peter Hohenstein

Research output: Contribution to journalArticlepeer-review

Abstract / Description of output

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.
Original languageEnglish
Pages (from-to)559-574
Number of pages16
JournalDevelopmental Cell
Volume21
Issue number3
DOIs
Publication statusPublished - Sept 2011

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