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Genomics study uncovers the transcription factors able to restore hearing in zebrafish

Written by Lauren Robertson, Science Writer.

Researchers at the National Human Genome Research Institute (NHGRI) have discovered a unique network of proteins responsible for restoring hearing in zebrafish. These proteins – otherwise known as transcription factors – are capable of controlling cell regeneration and could inform the development of potential treatments for hearing loss in humans.

Hear, hear!

One of the most common forms of sensory deficit in humans, hearing loss affects around 37.5 million Americans. Most cases of hearing loss are caused by damage to receptors in the inner ear known as “hair cells.” When mechanical vibrations (AKA sound) travels into our ears, these cells transduce the vibrations into an electrical signal that is then relayed to our brains. Unfortunately, once these cells are damaged, there’s no going back – at least not for most mammals.

Other vertebrates – such as the zebrafish – are able to regenerate hair cells after injury and recover their hearing. But the mechanisms behind this regenerative process remain unclear – so Erin Jimenez and her team at NHGRI decided to study them in more detail.

Figure 1: Confocal image of adult zebrafish hair cells (green) in the auditory organ of the inner ear. Credit: Erin Jimenez, Ph.D.

The transcription factor network

Single-cell epigenome and transcriptome data was captured at consecutive time points during hair cell regeneration. This allowed the team to get a good understanding of what was happening inside the cells during the unique process. They then used deep learning on regeneration-induced chromatin sequences that appeared to be involved, identifying a pattern of overlapping Sox and Six-family transcription factor (TFs) motif patterns.

TFs are basically proteins that turn genes on or off. Though scientists had previously identified some factors responsible in the regeneration process, they had not figured out where the gene encoding these factors were turned on and how they coordinated with other unknown TFs.

To get a clearer picture of how the hair cell regeneration process was working, the team used scRNA sequencing to study enhancer sequences within the zebrafish genome – these are parts of the genome that enable TFs to express a gene.

A 2.6 kb DNA enhancer was found upstream of the sox2 gene promoter. Crucially, when this enhancer region was deleted, the zebrafish were no longer able to regenerate their hair cells.

Regeneration restored

The researchers believe they can now explain what is happening inside the zebrafish’s inner ear. First, the Sox TFs initiate the regeneration response in surrounding support cells within the sensory epithelium. Then, the Sox and Six TFs coordinate and cause the support cells to change cell identity into a “progenitor” cell population. These progenitor cells are in a special transition state that allows them to re-enter mitosis when hair cells are depleted – forming a brand-new hair cell that restores hearing.

“We have identified a unique combination of transcription factors that trigger regeneration in zebrafish,” said Jimenez. “Further down the line, this group of zebrafish transcription factors might become a biological target that may lead to the development of novel therapy to treat hearing loss in humans.”

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