Abstract
The inner ear is a complex structure responsible for hearing and balance, and organ pathology is associated with deafness and balance disorders. To evaluate the role of epigenomic dynamics, we performed whole genome bisulfite sequencing at key time points during the development and maturation of the mouse inner ear sensory epithelium (SE). Our single-nucleotide resolution maps revealed variations in both general characteristics and dynamics of DNA methylation over time. This allowed us to predict the location of non-coding regulatory regions and to identify several novel candidate regulatory factors, such as Bach2, that connect stage-specific regulatory elements to molecular features that drive the development and maturation of the SE. Constructing in silico regulatory networks around sites of differential methylation enabled us to link key inner ear regulators, such as Atoh1 and Stat3, to pathways responsible for cell lineage determination and maturation, such as the Notch pathway. We also discovered that a putative enhancer, defined as a low methylated region (LMR), can upregulate the GJB6 gene and a neighboring non-coding RNA. The study of inner ear SE methylomes revealed novel regulatory regions in the hearing organ, which may improve diagnostic capabilities, and has the potential to guide the development of therapeutics for hearing loss by providing multiple intervention points for manipulation of the auditory system.
Highlights
The inner ear is a complex structure responsible for hearing and balance, and organ pathology is associated with deafness and balance disorders
To ensure that low methylated region (LMR) were representative of known distal regulatory elements, we examined whether they overlapped known DNase I Hypersensitive Sites (DHS) in the mouse genome, which are indicative of transcription factor (TF) binding
Our work provides the first DNA methylome map in the mammalian inner ear sensory epithelium (SE), covering two major transitions, the developmental embryonic stage between E16.5 and newborn (P0) mice, and across the maturation transition period soon after the onset of hearing
Summary
The inner ear is a complex structure responsible for hearing and balance, and organ pathology is associated with deafness and balance disorders. To evaluate the role of epigenomic dynamics, we performed whole genome bisulfite sequencing at key time points during the development and maturation of the mouse inner ear sensory epithelium (SE). Our single-nucleotide resolution maps revealed variations in both general characteristics and dynamics of DNA methylation over time This allowed us to predict the location of non-coding regulatory regions and to identify several novel candidate regulatory factors, such as Bach[2], that connect stage-specific regulatory elements to molecular features that drive the development and maturation of the SE. This study was designed to elucidate DNA methylation dynamics during mouse SE development and maturation To this end, we generated single nucleotide resolution genome-wide maps at key developmental time points and built a regulatory network underpinning tissue transitions throughout the developmental process that culminates in a functional, hearing inner ear. The results obtained from exploiting this unique resource shed new light on the complexity of developmental and pathological mechanisms of both hearing and deafness in humans
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