Sonic hedgehog (Shh) expression in the limb bud organizing center called the ZPA 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. 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 ETS 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.
- Silvia Peluso
- Adam Douglas
- Alison Hill
- Carlo De Angelis
- Benjamin L Moore
- Graeme Grimes
- Giulia Petrovich
- Abdelkader Essafi
- Robert E Hill
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Animal experimentation: Experiments using mice were conducted in accordance with the UK Animals (Scientific Procedures) Act 1986, with appropriate personal and project licences in place.
- Lee Niswander, University of Colorado Anschutz Medical Campus, United States
© 2017, Peluso et al.
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