Scientists identify unique set of proteins that restore hearing

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

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Study demonstrates how transcription factors support cell regeneration.

Researchers from the National Institutes of Health have identified a particular protein network that is required for cell regeneration to restore hearing in zebrafish. Researchers from the National Human Genome Research Institute (NHGRI) conducted the research, which could aid in the creation of treatments for human hearing loss. The results were recently published in the journal Cell genomics.

Many animals, such as zebrafish, can recover their hearing after injury through hair cell regeneration, however, human hair cell loss cannot be restored. The regenerative properties of zebrafish hair cells have inspired researchers to use this species to better understand some fundamental properties of regeneration.

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

Despite quite distinct appearances, humans and zebrafish have over 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 findings into humans.

Brightfield image of a two-day-old zebrafish embryo. Credit: Erin Jimenez, Ph.D.

Erin Jimenez, Ph.D., postdoctoral fellow in the lab of Shawn Burgess, Ph.D., principal investigator in the Translational and Functional Genomics Branch of the National Human Genome Research Institute (NHGRI), 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. “How and why regeneration occurs in these animals remains a mystery that many scientists would like to unravel.”

Using a combination of genomic techniques and computational machine learning, Jimenez and his collaborators discovered that hair cell regeneration in zebrafish relies on a network of proteins capable of switching genes on and off, called transcription factors. To correctly identify the transcription factors involved, the researchers first had to look at the enhancer sequences in the zebrafish genome.

If transcription factors are thought of as the keys that turn a car on and off, enhancement sequences are the car’s ignition switch. The two parts must interact to make a car work, much like transcription factors must bind to specific activator sequences to express a gene.

The researchers used new genomic techniques called single-cell

” data-gt-translate-attributes=”[{” attribute=””>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.

“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.