Hearing loss is one of the most common disabilities in the United States. It can be caused by the effects of aging, genetic mutations, environmental stress, or exposure to drugs such as platinum-based chemotherapy drugs. Researchers have been focusing their attention on several pathways with implications in development and regeneration. Now, researchers from the USC stem cell laboratory of Neil Segil, PhD, have discovered a natural barrier to the regeneration of the inner ear’s sensory cells, which are lost in hearing and balance disorders. Their mouse study may lead to new gene engineering approaches for regenerating the inner ear.

Their new study, “Enhancer decommissioning imposes an epigenetic barrier to sensory hair cell regeneration,” is published in Developmental Cell.

“Permanent hearing loss affects more than 60% of the population that reaches retirement age,” said Segil, who is a professor in the department of stem cell biology and regenerative medicine, and the USC Tina and Rick Caruso department of otolaryngology-head and neck surgery. “Our study suggests new gene engineering approaches that could be used to channel some of the same regenerative capability present in embryonic inner ear cells.”

“Adult mammalian tissues such as heart, brain, retina, and the sensory structures of the inner ear do not effectively regenerate, although a latent capacity for regeneration exists at embryonic and perinatal times,” wrote the researchers. “We explored the epigenetic basis for this latent regenerative potential in the mouse inner ear and its rapid loss during maturation.”

For the first few days of life, lab mice retain an ability for supporting cells to transform into hair cells through the process of transdifferentiation, which allows for regeneration. By one week of age, mice lose this regenerative capacity, and humans probably lose this ability before birth.

Postdoctoral scholar Litao Tao, PhD, graduate student Haoze (Vincent) Yu, and colleagues observed the neonatal changes that cause supporting cells to lose their potential for transdifferentiation.

The researchers hypothesized that epigenetic silencing may contribute to the age-dependent failure of hair cell regeneration in mammals. They found that “hair cell genes are silenced in supporting cells by active histone deacetylation and the presence of H3K27me3. However, the hair cell regulatory network remains epigenetically ‘poised’ and ‘primed’ by H3K4me3 and H3K4me1 at hair cell gene promoters and enhancers, respectively.”

With age, the supporting cells of the cochlea gradually lost H3K4me1, causing them to exit the primed state. However, if the scientists added a drug to prevent the loss of H3K4me1, the supporting cells remained temporarily primed for transdifferentiation. Supporting cells from the vestibular system were also still primed for transdifferentiation into adulthood.

“…These results, together with the work presented here, offer a glimpse of future hearing restoration strategies that make use of epigenetic manipulation by pharmaceutical inhibitors, epigenetic engineering strategies such as the CRISPR-dCAS9 system, and direct reprogramming,” concluded the researchers.

“Our study raises the possibility of using therapeutic drugs, gene editing, or other strategies to make epigenetic modifications that tap into the latent regenerative capacity of inner ear cells as a way to restore hearing,” said Segil. “Similar epigenetic modifications may also prove useful in other non-regenerating tissues, such as the retina, kidney, lung, and heart.”

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