Abstract
Background The mammalian inner ear is a complex morphological structure responsible for hearing and balance, and its pathology is associated with deafness and balance disorders. To evaluate the role of epigenomic dynamics in the development and maturation of mouse inner ear sensory epithelium, we performed whole-genome bisulfite sequencing on inner ear tissue, yielding temporal base-pair resolution methylomes at key developmental time points.
Results We found a late accumulation of non-CpG methylation, indicating a similarity between the inner ear sensory epithelium and neuronal tissue. Moreover, annotation of both unmethylated and low methylated regions pointed to regulatory elements active in the inner ear in proximity of and distal from transcriptional units. Finally, we identified differentially methylated regions across the transition periods. An analysis of these regions led us to identify several novel candidate regulatory factors, connecting regulatory elements from specific time points in development to molecular features that drive the development and maturation of the inner ear sensory epithelium. The GJB6 locus putative regulatory region was shown to upregulate distal GJB6 gene expression and a non-coding RNA.
Conclusions Our analysis of inner ear sensory epithelium DNA methylation sheds light on novel regulatory regions in the hearing organ, and may help boost diagnostic capabilities and guide the development of therapeutics for hearing loss, by providing multiple intervention points for manipulation of the auditory system.
Abbreviations
- SE
- sensory epithelium
- E
- embryonic day
- P
- postnatal day
- ES
- embryonic stem
- UMR
- unmethylated regions
- LMR
- low-methylated regions
- DHS
- DNase I hypersensitive sites (DHS)
- TSS
- transcription start sites
- CGI
- CpG island
- TF
- transcription factor
- TFBS
- transcription factor binding sites
- 3D
- three-dimensional
- DevTrans
- developmental transition
- MatTrans
- maturation transition
- DMR
- differentially methylated region
- TG
- target gene
- GO
- Gene Ontology
- LD
- linkage disequilibrium
- EVA
- enlarged vestibular aqueduct
- NHEK
- Normal Human Epidermal Keratinocytes
- gRNA
- guide RNAs
- WES
- whole exome sequencing
- WGS
- whole genome sequencing