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Enhancer activation by FGF signalling during otic induction.

Monica Tambalo1, Maryam Anwar1, Mohi Ahmed1

  • 1Centre for Craniofacial and Regenerative Biology, Faculty of Dental, Oral and Craniofacial Sciences, King's College London, London, SE1 9RT, UK.

Developmental Biology
|September 21, 2019
PubMed
Summary

Fibroblast growth factor (FGF) signaling induces ear progenitors by modifying chromatin. FGF signaling rapidly activates specific enhancers via AP1 and p300, promoting otic gene expression during vertebrate ear development.

Keywords:
Cis-regulatory elementsCranial gangliaEarGene networksHearingPlacode

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Area of Science:

  • Developmental Biology
  • Epigenetics
  • Molecular Biology

Background:

  • Vertebrate ear progenitors arise from the pre-placodal region and are induced by fibroblast growth factor (FGF) signaling.
  • The precise molecular mechanisms coordinating downstream target gene activation during otic induction remain largely unknown.

Purpose of the Study:

  • To investigate the molecular response of pre-placodal progenitors to FGF signaling.
  • To identify new direct and indirect FGF targets involved in otic induction.
  • To elucidate the role of chromatin modifications in FGF-mediated otic gene regulation.

Main Methods:

  • Multiplex NanoString analysis of over 200 transcripts defining various embryonic territories.
  • Chromatin immunoprecipitation sequencing (ChIP-seq) to examine changes in histone marks (H3K27ac).
  • Analysis of transcription factor recruitment (AP1, p300) to cis-regulatory elements.

Main Results:

  • FGF signaling rapidly alters the transcriptomic landscape of pre-placodal cells, identifying novel FGF targets.
  • FGF exposure leads to the deposition of active chromatin mark H3K27ac near FGF-responsive otic genes, while non-otic genes show depletion.
  • Genomic regions gaining H3K27ac function as cis-regulatory elements controlling spatio-temporal otic gene expression.
  • The transcription factor dimer AP1, upon FGF signaling, recruits histone acetyl transferase p300 to activate otic enhancers.

Conclusions:

  • FGF signaling is a key driver of ear induction, orchestrating changes in the chromatin landscape.
  • FGF signaling promotes enhancer activation and chromatin accessibility through specific transcription factor recruitment and histone modification.
  • This study reveals a mechanism by which FGF signaling establishes the epigenetic state necessary for otic gene expression and ear development.