Transcriptomic and epigenetic regulation of hair cell regeneration in the mouse utricle and its potentiation by Atoh1.

Hsin-I Jen,Andrew K Groves,Matthew C Hill,Chenghang Zong,Haoze V Yu,Kuanwei Sheng,Hongyuan Zhang,Wenjian Cao,Neil Segil,Litao Tao,James F Martin,Juan Llamas

doi:10.7554/elife.44328

Abstract

The mammalian cochlea loses its ability to regenerate new hair cells prior to the onset of hearing. In contrast, the adult vestibular system can produce new hair cells in response to damage, or by reprogramming of supporting cells with the hair cell transcription factor Atoh1. We used RNA-seq and ATAC-seq to probe the transcriptional and epigenetic responses of utricle supporting cells to damage and Atoh1 transduction. We show that the regenerative response of the utricle correlates with a more accessible chromatin structure in utricle supporting cells compared to their cochlear counterparts. We also provide evidence that Atoh1 transduction of supporting cells is able to promote increased transcriptional accessibility of some hair cell genes. Our study offers a possible explanation for regenerative differences between sensory organs of the inner ear, but shows that additional factors to Atoh1 may be required for optimal reprogramming of hair cell fate.

Highlights

Sensory hair cells are exquisitely sensitive mechanosensors present in the inner ear and lateral line organs of vertebrates
We show that the chromatin of hair cell gene loci in utricle supporting cells is maintained in a more accessible state than their counterparts in the mature cochlea, and that Atoh1 transduction of supporting cells can render the chromatin of some hair cell gene loci more accessible
We demonstrated that many hair cell genes can be activated in utricle supporting cells after culturing in the presence of gentamicin, and that transduction of Atoh1 can up-regulate additional hair cell genes, we observed that almost 1000 utricle hair cell genes were not significantly up-regulated in supporting cells in either condition (Figure 3B,C, Figure 6—figure supplement 1A,B)

Summary

Introduction

Sensory hair cells are exquisitely sensitive mechanosensors present in the inner ear and lateral line organs of vertebrates. They are extremely vulnerable to the mechanical trauma of environmental noise exposure, and to ototoxic aminoglycoside antibiotics and platinum-containing chemotherapeutics (Oesterle, 2013; Liberman, 2016; Francis and Cunningham, 2017; Jiang et al, 2017; Liberman, 2017; Sheth et al, 2017).

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