Epigenetic mechanisms underlying hearing impairment

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.

Hearing loss affects many people and is often due to hair cell (HC) loss in the cochlea. HCs cannot regenerate, while surrounding supporting cells (SCs) can undergo reprogramming to form new HCs, but this ability is lost shortly after birth. Major questions are: how to promote HC regeneration from endogenous sources and how to prevent HC and SC degeneration? Increasingly associated with disease and reprogramming, epigenetic changes are likely to play a crucial role.
We will study the chromatin remodellers Chd7 and -4, which when mutated in humans cause sensorineural hearing loss. CHD7 mutations are associated with CHARGE and other syndromes, while mutations in CHD4 cause CHARGE-like defects. Our data in mice indicate that without Chd7 hair cells die. This project will unravel the molecular function of Chd7 and -4 in the mouse ear to identify cell-specific targets and elucidate their mechanism by
i) deleting Chd7/4 in hair and supporting cells to characterise their phenotype
ii) determining the time when Chd7 function in vivo can be rescued
iii) examining the transcriptome changes in Chd7/4 mutant and control HCs and SCs at specific time points
Integration of these data is a powerful strategy to identify direct targets unique and in common to Chd4 and Chd7 and thus link hearing loss due to Chd7/4 mutations with downstream molecular events. These data provide a rich resource to use bioinformatics and modelling to unravel the gene networks downstream of Chd7 and -4 as the basis to discover new causative deafness genes and pathways. This research will not only elucidate the mechanism of sensorineural hearing loss in CHARGE and other syndromes, but also form the basis for restorative strategies. It will provide a road into understanding the epigenetic landscape of the normal and degenerating ear and thus have wide implications to develop regenerative or protective strategies to restore hearing.

The proposed research will identify how chromatin remodelling affects hearing and determine the underlying cellular and molecular causes of hearing loss. This will bring us a step closer towards finding an effective drug target for regenerating lost hair cells or preventing hair cell death. As a result, people with degenerating hair cells (whether due to trauma, genetic defects, or age-related hearing loss and associated cognitive decline), will greatly benefit from the research. To reach out to these vulnerable members of society and their carers/families, we will directly approach them in their own communities. Many adults and elderly who are not accustomed to the digital nature of today's information gathering are further isolated from research and education. Our approach described in 'pathways to impact' will engage them back into the community and give hope through Science that they are not neglected and researchers are undertaking the challenging task of finding treatments and cures. Through our past engagement with the younger generation and their parents, it became evident that there is a general lack of awareness and education. Schools are not equipped with the expertise or access to Scientists to provide specialist education. Therefore, we will provide the specialist education through creative and two-way participation in workshops to school children, teenagers and adults. Finally, health departments and professionals, charities and public advisory bodies can use the research findings to adopt/modify policies, advice and treatment strategies.