Summary: Congenital deafness affects roughly one in 1,000 babies and is often linked to genetic mutations, many of which remain unidentified. Researchers have now pinpointed a new set of candidate genes regulated by the protein Six1, which plays a critical role in inner ear development.
Using chick embryos, the team showed that Six1 activates genes necessary for forming ear structures, and many of these genes are also found in human ear progenitor cells. Remarkably, some of the DNA regions involved are conserved across species, hinting at their fundamental role in hearing development.
Key Facts:
- Six1 Role: The protein Six1 regulates genes essential for inner ear development, making its targets strong candidates for deafness-related mutations.
- Cross-Species Conservation: DNA regions controlling Six1 target genes are conserved between birds and humans, emphasizing their biological importance.
- Deafness Loci: Around 25% of Six1-regulated genes are located in chromosome regions previously linked to congenital hearing loss.
Source: King’s College London
Congenital deafness (hearing loss from birth) is common, impacting around one in 1,000 babies born in the UK. The condition affects communication, social and cognitive development of children and general quality of life.
It is largely caused by mutations in genes, but many of these genes remain to be discovered. Understanding the exact mutations that cause deafness could hold the key to devising treatments.
Professor Andrea Streit, expert in developmental neurobiology at King’s College London, said: “Human genetics approaches have identified hundreds of ‘deafness loci’ – regions on chromosomes associated with deafness.
These regions contain many genes, and the challenge is to identify the gene that causes deafness when mutated.”
The study, led by King’s College London in collaboration with George Washington University, US, discovered new candidates for these so called ‘deafness genes’.
With previous research identifying mutations in a protein, Six1, causing hearing loss, the team focused their investigation on the genes regulated by this protein.
The researchers used computer-based methods to predict more than 150 potential Six1 targets in ear progenitor cells (cells which eventually form the entire inner ear) from chick embryos.
Selecting four of those targets for further investigation, they revealed that Six1 binds to the DNA regions that regulate their expression and that reducing levels of Six1 stopped these genes from being activated.
The team then showed that the vast majority of the genes found in chick are also expressed in human ear progenitors, and that a quarter of them fall into the chromosome regions associated with deafness.
Professor Andrea Streit said: “It was very exciting to find that some of the genes regulated by Six1 are located in regions deafness loci. This makes them priority candidates for being causative genes of congenital hearing loss.”
The scientists also discovered that some of the DNA regions that control Six1 target gene expression are conserved in birds and humans.
This finding suggests that despite 600 million years of evolution, Six1 and its molecular mechanisms are similar in both birds and humans. They may therefore control fundamental biological processes in ear development.
Professor Andrea Streit, added: “It is unusual that regulatory sections of DNA, like the ones we studied, are highly conserved across species. The fact that we find them to be very similar from birds to humans indicates their critical role.”
The team believe further research into Six1 and the genes it regulates could provide insight into the molecular mechanisms that control how the ear normally develops.
About this genetics and deafness research news
Author: Tanya Wood
Source: King’s College London
Contact: Tanya Wood – King’s College London
Image: The image is credited to Neuroscience News
Original Research: Open access.
“Targets of the transcription factor Six1 identify previously unreported candidate deafness genes” by Andrea Streit et al. Development
Abstract
Targets of the transcription factor Six1 identify previously unreported candidate deafness genes
Branchio-otic (BOS) and branchio-oto-renal (BOR) syndromes are autosomal dominant disorders featuring multiple birth defects including ear, renal and branchial malformations.
Mutations in the homeodomain transcription factor SIX1 and its co-factor EYA1 have been identified in about 50% of individuals with BOS or BOR, while causative mutations are unknown in the other half.
We hypothesise that SIX1 target genes represent new BOS and BOR candidates.
Using published transcriptomic and epigenomic data from chick ear progenitors, we first identify putative Six1 targets.
Next, we provide evidence that Six1 directly regulates some of these candidates: Six1 binds to their enhancers, and functional experiments in Xenopus and chick confirm that Six1 controls their expression.
Finally, we show that most putative chick Six1 targets are also expressed in the human developing ear and are associated with known deafness loci.
Together, our results not only characterise the molecular mechanisms that mediate Six1 function in the developing ear, but also provide new candidates for human congenital deafness.
