Scientists Identify a Unique Set of Proteins That Restore Hearing

A Study Demonstrates How Transcription Factors Support Cell Regeneration

Researchers at the National Institutes of Health have identified a particular protein network that is necessary for cell regeneration to restore hearing in zebrafish. Researchers at the National Human Genome Research Institute (NHGRI) led the research, which may help in the creation of human hearing loss treatments. The findings were recently published in the journal Cell Genomics. 

Many animals, like zebrafish, may recover their hearing after injury through the regeneration of hair cells, however, human hair cell loss cannot be restored. The regenerating properties of zebrafish hair cells inspired researchers to use this species to better understand certain fundamental properties of regeneration.

About 37.5 million Americans suffer from hearing loss, and the majority of these instances are caused by the loss of hearing receptors called “hair cells” in the inner ear. When sound enters our ears, bristles that protrude from these tiny hair cells move and bend, causing electric signals to be sent through nerves and into our brains that allow us to process sound.

Despite having quite distinct appearances, humans and zebrafish have more than 70% of the same genes at the genomic level. This genomic similarity allows researchers to better understand the biology of cell regeneration in zebrafish before translating their results to humans.

Erin Jimenez, Ph.D., a postdoctoral fellow in the laboratory of Shawn Burgess, Ph.D., senior investigator in the National Human Genome Research Institute’s (NHGRI) Translational and Functional Genomics Branch, led the study in collaboration with researchers Ivan Ovcharenko, Ph.D., and Wei Song, Ph.D., at the National Library of Medicine’s National Center for Biotechnology Information.

“Humans and other mammals are born with a set number of hair cells that are slowly lost through aging and trauma. However some animals, such as zebrafish, can regenerate hair cells and recover hearing after injury,” said Burgess. “How and why regeneration happens in these animals remains a mystery that many scientists would like to unravel.”

Identifying Transcription Factors Behind Hair Cell Regeneration

Using a combination of genomic techniques and computational-based machine learning, Jimenez and her collaborators found that hair cell regeneration in zebrafish relied on a network of proteins that can switch genes on and off, known as transcription factors. To properly identify which transcription factors were at play, the researchers first had to look at the enhancer sequences within the zebrafish genome.

If transcription factors are thought of as the keys that turn a car on and off, enhancer sequences are the car’s ignition switch. Both parts need to interact to make a car run, just like how transcription factors need to bind to specific enhancer sequences to express a gene.

The researchers used new genomic techniques called single-cell RNA sequencing and single-cell assay for transposase-accessible chromatin using sequencing to identify the enhancer sequences and their corresponding transcription factors that play a role in hair cell regeneration.

Sox and Six Transcription Factors: Keys to Hair Cell Regeneration

“Our study identified two families of transcription factors that work together to activate hair cell regeneration in zebrafish, called Sox and Six transcription factors,” said Jimenez.

First, the Sox transcription factors initiate the regeneration response in surrounding cells, called support cells. Next, the Sox and Six transcription factors cooperate to turn those support cells into hair cells.

When hair cells die in zebrafish, nearby support cells start replicating. These support cells are like stem cells because of their ability to become other cell types. Researchers had identified some of the factors that convert support cells into hair cells, but what was not understood is how and where the genes encoding those factors turn on and are coordinated with other unknown factors.

“We have identified a unique combination of transcription factors that trigger regeneration in zebrafish. 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,” Jimenez said.

Reference: “A regulatory network of Sox and Six transcription factors initiate a cell fate transformation during hearing regeneration in adult zebrafish” by Erin Jimenez, Claire C. Slevin, Wei Song, Zelin Chen, Stephen C. Frederickson, Derek Gildea, Weiwei Wu, Abdel G. Elkahloun, Ivan Ovcharenko and Shawn M. Burgess, 22 August 2022, Cell Genomics.
DOI: 10.1016/j.xgen.2022.100170

The study was funded by the National Human Genome Research Institute.

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