Enhancer activation by FGF signalling during otic induction

Monica Tambalo,Maryam Anwar,Mohi Ahmed,Andrea Streit

doi:10.1016/j.ydbio.2019.09.006

Monica Tambalo, Maryam Anwar + Show 2 more

Open Access

https://doi.org/10.1016/j.ydbio.2019.09.006

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Abstract

Vertebrate ear progenitors are induced by fibroblast growth factor signalling, however the molecular mechanisms leading to the coordinate activation of downstream targets are yet to be discovered. The ear, like other sensory placodes, arises from the pre-placodal region at the border of the neural plate. Using a multiplex NanoString approach, we determined the response of these progenitors to FGF signalling by examining the changes of more than 200 transcripts that define the otic and other placodes, neural crest and neural plate territories. This analysis identifies new direct and indirect FGF targets during otic induction. Investigating changes in histone marks by ChIP-seq reveals that FGF exposure of pre-placodal cells leads to rapid deposition of active chromatin marks H3K27ac near FGF-response genes, while H3K27ac is depleted in the vicinity of non-otic genes. Genomic regions that gain H3K27ac act as cis-regulatory elements controlling otic gene expression in time and space and define a unique transcription factor signature likely to control their activity. Finally, we show that in response to FGF signalling the transcription factor dimer AP1 recruits the histone acetyl transferase p300 to selected otic enhancers. Thus, during ear induction FGF signalling modifies the chromatin landscape to promote enhancer activation and chromatin accessibility.

Highlights

The vertebrate inner ear is critical to relay auditory and vestibular information from the environment to the brain
We study the changes in H3K27ac, a histone mark associated with active enhancers (Creyghton et al, 2010; Kharchenko et al, 2011; Rada-Iglesias et al., 2012; Rada-Iglesias et al, 2011; Zentner et al, 2011), as pre-placodal cells acquire otic-epibranchial progenitors (OEPs) fate in response to Fibroblast Growth Factor (FGF) signalling
We find that FGF rapidly induces dynamic changes at thousands of genomic regions with a marked gain of H3K27 acetylation near OEP genes

Summary

INTRODUCTION

The vertebrate inner ear is critical to relay auditory and vestibular information from the environment to the brain. Our findings suggest that AP1 may play a key role in this process: upon FGF signalling, AP1 recruits the histone acetylase p300 to some selected ear enhancers, which in turn promotes H3K27 acetylation associated with increased chromatin accessibility and enhancer activation Together these findings highlight that during ear induction, the initial response to Erk/MAPK signalling directly activates ear-specific enhancers, providing a molecular mechanism for rapid activation of gene expression downstream of FGF. These observations may impact on a variety of diseases and developmental disorders where FGFs play a major role

RESULTS

DISCUSSION

MATERIALS AND METHODS

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