Scientists identify a unique set of proteins that restore hearing

Scientists identify a unique set of proteins that restore hearing
Zebrafish hair cells

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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A study demonstrates how transcription factors support cell regeneration.

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

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

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

Despite having quite different 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.

zebrafish embryo

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

Erin Jiménez, Ph.D., a postdoctoral fellow in the lab of Shawn Burgess, Ph.D., a 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 Center for Biotechnology Information at the National Library of Medicine.

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

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

If transcription factors are considered to be the keys that turn a car on and off, enhancer sequences are the car’s ignition switch. Both parts must interact to make a car work, just as transcription factors must bind to specific enhancer sequences to express a gene.

The researchers used new genomic techniques called single cell.[{” 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.

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