A regulatory network of Sox and Six transcription factors support auditory cell regeneration

Posted by Caroline on November 25th, 2022

Researchers at the National Institutes of Health have identified a specific network of proteins necessary for zebrafish cells to regenerate and restore hearing. Researchers at the National Human Genome Research Institute (NHGRI) led the study, which may help create treatments for hearing loss in humans. The findings were recently published in Cell Genomics.

Many animals, such as zebrafish, can restore hearing through hair cell regeneration after injury, but hair cell loss in humans cannot be restored. The regenerative properties of zebrafish hair cells have inspired researchers to use this species to better understand certain basic properties of regeneration.

About 37.5 million Americans suffer from hearing loss, most of which is caused by the loss of auditory receptors called "hair cells" in the inner ear. When sound enters our ears, hairs protruding from these tiny hair cells move and bend, causing electrical signals to be sent to our brains through nerves, allowing us to process sound.

Although humans and zebrafish have distinct appearances, they possess more than 70% of the same genes at the genomic level. This genomic similarity allows researchers to better understand the biology of zebrafish cell regeneration before translating the findings into humans.

Dr. Erin Jimenez is a postdoctoral fellow in the laboratory of Dr. Shawn Burgess, a senior researcher in the Translational and Functional Genomics Branch of the National Human Genome Research Institute (NHGRI), who led the study in collaboration with Dr. Ivan Ovcharenko and Dr. Wei Song of 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 slowly disappear with age and trauma. However, some animals, such as zebrafish, can regenerate hair cells and restore hearing after injury," Burgess said. "How and why these animals regenerate remains a mystery that many scientists want to solve."

Through a combination of genomic technology and computer-based machine learning, Jimenez and her collaborators found that hair cell regeneration in zebrafish depends on a protein network that switches genes and is called transcription factors. To correctly identify which transcription factors are at work, researchers first have to look at enhancer sequences in the zebrafish genome.

If transcription factors are considered keys to turning cars on and off, enhancer sequences are ignition switches for cars. These two parts need to interact to allow the car to operate, just as transcription factors need to bind specific enhancer sequences to express genes. The researchers used single-cell RNA sequencing and single-cell detection of transposase accessible chromatin to determine enhancer sequences and their corresponding transcription factors by sequencing that play a role in hair cell regeneration.

"Our study identifies two families of transcription factors that act together to activate hair cell regeneration in zebrafish and are called Sox and Six transcription factors," Jimenez said.

First, Sox transcription factors initiate regenerative responses in surrounding cells, called Sertoli cells. Next, Sox and Six transcription factors cooperate to convert these Sertoli cells into HCs.

When hair cells die in zebrafish, nearby Sertoli cells begin to replicate. These Sertoli cells are like stem cells because they have the ability to become other types of cells. Researchers have identified a number of factors that transform Sertoli cells into HCs, but it is unclear how and where the genes encoding these factors are initiated and coordinated with other unknown factors.

"We have identified a unique combination of transcription factors that can trigger regeneration in zebrafish. Further, this group of zebrafish transcription factors may become a biological target that may lead to the development of new therapies for the treatment of hearing loss in humans," Jimenez said.

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