Hearing loss is a large health issue in the US with approximately 36 million adults reporting some loss. Much of this deafness is caused by loss of the sensory hair cells in the inner ear either from noise or drug damage or just aging. Much research has aimed at replacing these lost cells. Another approach is to restart the developmental program by which these cells develop to begin with. The inner ear is a highly complex tissue, with many different cell types. Understanding the development of this complex organ will ultimately require characterization of gene expression and its regulation in developing and mature inner ear cell types. DNase I hypersensitivity mapping (DNase I-seq) has recently been developed to map enhancers of genes in particular tissues at particular stages of development. In this proposed research we aim to map the enhancers that are used in the inner ear during development. Knowledge of the way genes are regulated in the inner ear may provide us with additional targets for manipulation in our attempts to restore hearing and balance function. This research proposes to completely characterize the enhancers using DNase I hypersensitivity mapping, RNA-seq and using mutant mice that lack sensory domains to determine which are the critical genes. This will be accomplished with the following three specific aims:
Aim 1. Mapping the accessible chromatin in the inner ear at three developmental ages.
Aim 2. Mapping DNase I hypersensitive regions in a mutant lacking the sensory domain.
Aim 3. Characterization of enhancer activity in explant culture.
In humans, loss of the hair cells in the inner ear leads to hearing and balance impairment, since these cells do not regenerate by contrast, in non-mammalian vertebrates, like birds and fish, damaged auditory hair cells are regenerated very efficiently from the surrounding supporting cells. This proposed research aims to identify enhancers of genes important in inner ear development. We are particularly interested in identifying regulatory regions for genes that may be manipulated to restore function after damage to hair cells.
