title: A wt1-controlled chromatin switching mechanism underpins tissue-specific wnt4 activation and repression.
abstract: 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.
authors.affiliation: MRC Human Genetics Unit and Institute for Genetics and Molecular Medicine, Western General Hospital, Edinburgh EH4 2XU, UK. aessaﬁ@hgu.mrc.ac.uk
authors.forename: Abdelkader
authors.initials: A
authors.lastname: Essafi
authors.forename: Anna
authors.initials: A
authors.lastname: Webb
authors.forename: Rachel L
authors.initials: RL
authors.lastname: Berry
authors.forename: Joan
authors.initials: J
authors.lastname: Slight
authors.forename: Sally F
authors.initials: SF
authors.lastname: Burn
authors.forename: Lee
authors.initials: L
authors.lastname: Spraggon
authors.forename: Victor
authors.initials: V
authors.lastname: Velecela
authors.forename: Ofelia M
authors.initials: OM
authors.lastname: Martinez-Estrada
authors.forename: John H
authors.initials: JH
authors.lastname: Wiltshire
authors.forename: Stefan G E
authors.initials: SG
authors.lastname: Roberts
authors.forename: David
authors.initials: D
authors.lastname: Brownstein
authors.forename: Jamie A
authors.initials: JA
authors.lastname: Davies
authors.forename: Nicholas D
authors.initials: ND
authors.lastname: Hastie
authors.forename: Peter
authors.initials: P
authors.lastname: Hohenstein