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Fibroblast growth factors (FGFs) prime the limb specific Shh enhancer for chromatin changes that balance histone acetylation mediated by E26 transformation-specific (ETS) factors

Research output: Contribution to journalArticle

  • Silvia Peluso
  • Adam Douglas
  • Alison Hill
  • Carlo De Angelis
  • Benjamin L Moore
  • Graeme Grimes
  • Giulia Petrovich
  • Abdelkader Essafi
  • Robert E Hill
Original languageEnglish
Article numbere28590
Number of pages22
JournaleLife
Volume6
Early online date26 Sep 2017
DOIs
DateAccepted/In press - 25 Sep 2017
DateE-pub ahead of print - 26 Sep 2017
DatePublished (current) - 27 Oct 2017

Abstract

Sonic hedgehog (Shh) expression in the limb bud organizing centre called the zone of polarizing activity is regulated by the ZRS enhancer. Here, we examine in mouse and in a mouse limb-derived cell line the dynamic events that activate and restrict the spatial activity of the ZRS. Fibroblast growth factor (FGF) signalling in the distal limb primes the ZRS at early embryonic stages maintaining a poised, but inactive state broadly across the distal limb mesenchyme. The E26 transformation-specific transcription factor, ETV4, which is induced by FGF signalling and acts as a repressor of ZRS activity, interacts with the histone deacetylase HDAC2 and ensures that the poised ZRS remains transcriptionally inactive. Conversely, GABPα, an activator of the ZRS, recruits p300, which is associated with histone acetylation (H3K27ac) indicative of an active enhancer. Hence, the primed but inactive state of the ZRS is induced by FGF signalling and in combination with balanced histone modification events establishes the restricted, active enhancer responsible for patterning the limb bud during development.

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