Epigenetic Influences on Sensory Regeneration: Histone Deacetylases Regulate Supporting Cell Proliferation in the Avian Utricle

Abstract

The sensory hair cells of the cochlea and vestibular organs are essential for normal hearing and balance function. The mammalian ear possesses a very limited ability to regenerate hair cells and their loss can lead to permanent sensory impairment. In contrast, hair cells in the avian ear are quickly regenerated after acoustic trauma or ototoxic injury. The very different regenerative abilities of the avian vs. mammalian ear can be attributed to differences in injury-evoked expression of genes that either promote or inhibit the production of new hair cells. Gene expression is regulated both by the binding of cis-regulatory molecules to promoter regions as well as through structural modifications of chromatin (e.g., methylation and acetylation). This study examined effects of histone deacetylases (HDACs), whose main function is to modify histone acetylation, on the regulation of regenerative proliferation in the chick utricle. Cultures of regenerating utricles and dissociated cells from the utricular sensory epithelia were treated with the HDAC inhibitors valproic acid, trichostatin A, sodium butyrate, and MS-275. All of these molecules prevent the enzymatic removal of acetyl groups from histones, thus maintaining nuclear chromatin in a "relaxed" (open) configuration. Treatment with all inhibitors resulted in comparable decreases in supporting cell proliferation. We also observed that treatment with the HDAC1-, 2-, and 3-specific inhibitor MS-275 was sufficient to reduce proliferation and that two class I HDACs-HDAC1 and HDAC2-were expressed in the sensory epithelium of the utricle. These results suggest that inhibition of specific type I HDACs is sufficient to prevent cell cycle entry in supporting cells. Notably, treatment with HDAC inhibitors did not affect the differentiation of replacement hair cells. We conclude that histone deacetylation is a positive regulator of regenerative proliferation but is not critical for avian hair cell differentiation.

Histone Deacetylase Inhibitor Induces the Expression of Select Epithelial Genes in Mouse Utricle Sensory Epithelia-Derived Progenitor Cells

“…Second, TSA can arrest the cell cycle in a variety of cell types (Kong et al, 2014;Sikandar et al, 2011;Smith et al, 2014). For instance, in cochlear and vestibular tissue explant cultures, TSA showed the ability to decrease supporting cell proliferation (Slattery et al, 2009). In our study, MUCs presented a dose-response to TSA treatment.…”

Effects of retinoic acid and butyric acid on the expression of prestin and gata‐3 in organotypic cultures of the organ of corti of newborn rats

“…Experimental findings and clinical observations support the assumption that butyric acid may influence the inner ear. Recently, it has been shown that histone deacetylases regulate supporting cell proliferation in the avian utricle (Slattery et al, 2009). Sodium butyrate prevented cisplatin-or gentamicin-induced damage to hearing in guinea pigs and mice (Drottar et al, 2006).…”

“…The cofactors associated with the liganded nuclear factors show histone acetyltransferase (HAT) or histone deacetylases (HDAC) activity (Garcia-Villalba et al, 1997). The coordinated activation or repression of nuclear transcription factors by histone modification is an important transcription-regulating mechanism (Halili et al, 2009;Slattery et al, 2009). Whereas coactivators include HAT activity, corepressors appear to be able to recruit HDAC.…”

Insights into inner ear-specific gene regulation: Epigenetics and non-coding RNAs in inner ear development and regeneration

“…Treatment of hair cell-damaged chicken utricle with broad spectrum HDAC inhibitors or class I selective HDAC inhibitors resulted in a decrease in supporting cell proliferation, but did not affect the differentiation of replacement hair cells [143]. In developing zebrafish, class I HDACs, HDAC1 and HDAC3 are selectively expressed in lateral line primordium and neuromast [144, 145].…”