Integrative functional transcriptomic analyses implicate shared molecular circuits in sensorineural hearing loss
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA807641 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR18051541_1.fastq.gz | Fastqsanger.gz | |||
| SRR18051541_2.fastq.gz | Fastqsanger.gz | |||
| SRR18051542_1.fastq.gz | Fastqsanger.gz | |||
| SRR18051542_2.fastq.gz | Fastqsanger.gz | |||
| SRR18051543_1.fastq.gz | Fastqsanger.gz |
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Project description:Aging, noise exposure, and ototoxic drugs represent the three main causes of SNHL, leading to substantial similarities in pathophysiological characteristics of cochlear degeneration. Although the common molecular mechanisms are widely assumed to underlie these similarities, its validity lacks systematic examination. To address this question, we generated three SNHL mouse models from aging, noise exposure, and cisplatin ototoxicity and constructed gene coexpression networks for the cochlear transcriptome data across different hearing-damaged stages.
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Project description:Sensorineural hearing loss (SNHL) is referred to as the most common type of hearing loss and typically occurs when the inner ear or the auditory nerve is damaged. Aging, noise exposure, and ototoxic drugs represent three main causes of SNHL, leading to substantial similarities in pathophysiological characteristics of cochlear degeneration. Although the common molecular mechanisms are widely assumed to underlie these similarities, its validity lacks systematic examination. To address this question, we generated three SNHL mouse models from aging, noise exposure, and cisplatin ototoxicity, respectively. Through constructing gene co-expression networks for the cochlear transcriptome data across different hearing-damaged stages, the three models are found to significantly correlate with each other in multiple gene co-expression modules that implicate distinct biological functions, including apoptosis, immune, inflammation, and ion transport. Bioinformatics analyses reveal several potential hub regulators, such as IL1B and CCL2, both of which are verified to contribute to apoptosis accompanied by the increase of (ROS) in in vitro model system. Our findings disentangle the shared molecular circuits across different types of SNHL, providing potential targets for the broad effective therapeutic agents in SNHL.
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Project description:Alternative splicing contributes to gene expression dynamics in many tissues, yet its role in auditory development remains unclear. We performed whole exome sequencing in individuals with sensorineural hearing loss (SNHL) and identified pathogenic mutations in Epithelial Splicing Regulatory Protein 1 (ESRP1). Patient derived induced pluripotent stem cells showed alternative splicing defects consistent with impaired ESRP1 function. To determine how mutations in ESRP1 cause hearing loss we evaluated Esrp1-/- mouse embryos and uncovered alterations in cochlear morphogenesis, auditory hair cell differentiation and cell fate specification. Transcriptome analysis revealed impaired expression and splicing of genes with essential roles in inner ear development and auditory function. In particular, aberrant splicing of Fgfr2 blocked stria vascularis formation due to erroneous ligand usage, which was corrected by reducing Fgf9 gene dosage. These findings implicate mutations in ESRP1 as a novel cause of SNHL and demonstrate the complex interplay between alternative splicing, inner ear development, and auditory function.
2017-09-01 | GSE90821 | GEO
Project description:Background The genetic diversity of loci and mutations underlying hereditary hearing loss is an active area of investigation. To identify loci associated with predominantly non-syndromic sensorineural hearing loss, we performed exome sequencing of families and of single probands, as well as copy number variation (CNV) mapping in a case-control cohort. Results Analysis of three distinct families revealed several candidate loci in two families and a single strong candidate gene, MYH7B, for hearing loss in one family. MYH7B encodes a Type II myosin, consistent with a role for cytoskeletal proteins in hearing. High-resolution genome-wide CNV analysis of 150 cases and 157 controls revealed deletions in genes known to be involved in hearing (e.g. GJB6, OTOA, and STRC, encoding connexin 30, otoancorin, and stereocilin, respectively), supporting CNV contributions to hearing loss phenotypes. Additionally, a novel region on chromosome 16 containing part of the PDXDC1 gene was found to be frequently deleted in hearing loss patients (OR = 3.91, 95% CI: 1.62-9.40, p = 1.45 x 10-7). Conclusions We conclude that many known as well as novel loci and distinct types of mutations not typically tested in clinical settings can contribute to the etiology of hearing loss. Our study also demonstrates the challenges of exome sequencing and genome-wide CNV mapping for direct clinical application, and illustrates the need for functional and clinical follow-up as well as curated open-access databases. Single replicates of 151 non-syndromic hereditary hearing loss cases and 157 controls with normal hearing were analyzed.
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Project description:<p>Our goal is to find genes responsible for non-syndromic sensorineural hearing loss. Blood samples were collected from the JS6 family affected with hearing loss. The family is of Caribbean Hispanic ethnicity. Family JS6 consisted of two deaf siblings, JS6.001 (Male) and JS6.002 (Female) and healthy parents, JS6.100 (mother) and JS6.200 (father). The siblings had no other medical findings. Audiometry tests and Rinne and Weber tuning fork tests identified sensorineural hearing loss in the two siblings. We performed whole exome sequencing of the four individuals and identified a recessive mutation, p.(Arg186Trp), in the CIB2 gene in the two affected siblings. Both parents were unaffected carriers. </p>
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