Today's journal article
Foo CZ, Duggan A, Bartom ET, Tao L, García-Añoveros J. Differential Chromatin Accessibility, "Gene Expression, and mRNA Splicing Between Developing Cochlear Inner and Outer Hair Cells."
- J Assoc Res Otolaryngol. 2025 Sep 5.
- doi: 10.1007/s10162-025-01005-z. Epub ahead of print. PMID: 40911150.
- available online at: https://link.springer.com/article/10.1007/s10162-025-01005-z
- Their data is also publicly available at: https://igvviewer.s3.us-east-2.amazonaws.com/index.html
Why I picked this article
Our inner ear organ for hearing, the cochlea, has two types of auditory sensory cells: inner hair cells and outer hair cells. They share some similar basic characteristics, like the presence of stereocilia ("the hairs!") and expression of key membrane proteins. But at the same time, outer and inner hair cells are very different in appearance and physiological function. Most notably, the outer hair cells have the ability to change their body length, which enables them to function as the cochlear amplifier. Inner hair cells are full of synaptic connections from auditory neurons. So they are both highly specialised cell tyeps.
It's really interesting to think about how such specialised cells can develop, considering all our cells in the body share the same genome within the individual. The biological process of immature cells becoming more mature and specialised, is called "differentiation". Cell differentiation is regulated by a type of protein called "transcription factors", which bind to a particular part of the DNA to facilitate the production of target proteins, which then allow cells to perform specialised functions.
This publication describes some differences that regulate the differentiation of inner hair cells and outer cells based on large datasets generated from the mouse cochlea. Cell differentiation is an absolutely fascinating area of research!
Some of the research findings
Methods:
- RNASeq data obtained from separate pools of inner and outer hair cells from mouse cochlea.
- RNASeq data were analysed against Genomic data, using edgeR.
Finding about gene expression ("gene" is a region of DNA responsible for a particular protein):
- 752 genes were enriched in the inner hair cells
- after further comparison with databases and in situ hybridization, Fgf8 was specific to inner hair cells.
- 122/752 IHC-enriched genes were specific to hair cells.
- 531 genes were enriched in the outer hair cells
- after further comparisons and in situ hybridization, Neurod6 and Insm1 were specific to outer hair cells.
- 75/531 OHC-enriched genes were specific to hair cells.
Authors also investigated differential RNA splicing (= different ways in which RNA is processed, to result in slightly different protein) with rMATS, and found:
- 2396 different splicing between the inner hair cells and the outer hair cells.
- These were across 1406 genes.
- They provide some interesting examples such as Snap23 (for making protein important for synapse function) and Bcl2 (mitochondria protein).
The research group then compared the chromatin accessibility, which regulates to how proteins are produced from the gene.
- Assay for transposase-accessible chromatin using sequencing (ATAC-seq) on the inner hair cells (P0 mouse pup, 2932 inner hair cells were pooled) and outer hair cells (same, 11,706 outer hair cells were pooled).
- Regions of accessible chromatin were identified - 3348 peaks were enriched in the inner hair cells and 2085 were enriched in the outer hair cells.
- For some examples like Atoh1 and Pou4f3, both known to be important for hair cell development, were similar between inner hair cells and outer hair cells.
- For Fgf8 which was found to be inner hair cell specific, the gene and nearby region on the DNA was very chromatin accessible.
The authors conducted a great cross-comparison between ATAC-seq data and RNA-seq data to validate observations and the candidates for the inner hair cell-specific & the outer hair cell-specific genes.
Haruna's takeaway
... so much DATA!!!
There are tables and supplementary tables that describe the top candidates identified as being the inner or outer hair cell specific. Many candidates are very familiar with us, like synaptic proteins and ion channels, but also include ones that are not familiar. This publication is a salivating, exciting paper for those who are transcription factor & cell differentiation maniacs, because looking at these tables and supplementary data for something interesting would be very fun. With the original data available publicly through their website, we could make use of it to discover some interesting things.
For our interest, it is interesting to spot P2rx5, the P2X5 receptor subtype gene, as one enriched in inner hair cells Table 1. P2X5 antibodies are unreliable, and we have not been able to look at this protein in the cochlea in our group. P2X receptor proteins are also found differently between the mature and immature cochlear regions.
Cell differentiation and its regulation are very interesting. And many researchers also dream of its use; if we can fully understand how specialised hair cells develop, we may then be able to re-create them for regenerative medicine.
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This is Haruna's 4/100 of the 100-day challenge to post a science blog article every day! I love inner ear biology & cochlear physiology.