Epigenetic mechanisms underlying hearing impairment

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Sound and the perception of hearing is an extremely important means of communication, and losing the ability to hear often leads to social isolation and psychological trauma. There are many causes of hearing loss. Some, like listening to loud music, is preventable. Others, like genetic disorders and the normal process of ageing, are beyond our control. Hearing loss is therefore a major health concern and yet we are still unable to prevent or restore hearing successfully after damage to the ear. However, the more we understand about the genes that cause hearing loss in ageing and genetic disorders, the closer we can get to discovering ways of preventing and restoring hearing. This research project proposes to study how two genes called Chd7 and Chd4 control hearing and cause hearing loss in genetic disorders such as CHARGE syndrome using mouse models that resembles human CHARGE syndrome.The project will use genetic tools to inactivate Chd7 and Chd4 in different cells of the ear to study how Chd7/4 affects survival of cells that perceive sound and how these molecules act to maintain their function. This will provide an entry point to understand how these processes are controlled. The project will investigate the importance of both factors in fine-tuning the levels of many genes required for development and survival of cells in the ear that are essential for hearing. Combining state of the art molecular techniques with genetically modified mice will allow isolation of different cell types in the ear and identify which genes change when Chd7 or Chd4 are deleted. This is a powerful approach that will not only provide insight into the function of Chd7 and Chd4, but also provide new tools to design strategies to restore hearing. Chd7 and -4 belong to a family of proteins that change the DNA without changing its sequence. This is called epigenetic change, and such changes are reversible as they do not affect the DNA sequence. Since Chd7 and -4 mediate reversible processes, they are potentially amenable to therapeutic drug treatments. There are many molecules that work in a similar fashion and understanding the function of Chd7/4 may also shed light on the epigenetic changes that accompany ear development and ageing. Therefore, this research is expected to have widespread implications on hearing research and our understanding of hearing loss during ageing.In summary, while this is fundamental research, it is necessary to understand the causes of hearing loss in mammals as it may lead to developing new strategies to restore hearing in the elderly as well as in genetic disorders like CHARGE.