A unique set of hearing-restoring proteins, transcription factors, support hearing cell regeneration

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

Many animals, such as zebrafish, can restore hearing through the regeneration of hair cells after injury, but the loss of hair cells in humans cannot be recovered
.
The regenerative properties of zebrafish hair cells inspired researchers to use this species to better understand some of the fundamental properties
of regeneration.

About 37.
5 million Americans suffer from hearing loss, most of which is caused
by the loss of hearing receptors called "hair cells" in the inner ear.
When sound enters our ears, the hairs that protrude from these tiny hair cells move and bend, causing electrical signals to be sent through nerves to our brain, allowing us to process sounds
.

Despite the very different appearances of humans and zebrafish, at the genomic level, they share more than 70% of the same genes
.
This genomic similarity allowed the researchers to better understand the biology
of zebrafish cell regeneration before translating the findings to humans.

Dr.
Erin Jimenez, a postdoc in the lab of Shawn Burgess, Ph.
D.
, a senior investigator in the Division of Translational and Functional Genomics at the National Human Genome Research Institute (NHGRI), led the study
in collaboration with Dr.
Ivan Ovcharenko and Dr.
Wei Song of the National Center for Biotechnology Information at the U.
S.
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 is still a mystery
that many scientists want to solve.
"

Through a combination of genomic technology and compute-based machine learning, Jimenez and her collaborators found that hair cell regeneration in zebrafish relies on a network of proteins that switch genes on and off, called transcription factors
.
To properly identify which transcription factors are at work, researchers first had to look at the enhancer sequences
in the zebrafish's genome.

If the transcription factor is considered the key to turning the car on and off, the enhancer sequence is the ignition switch
for the car.
These two parts need to interact to get the car running, just as
transcription factors need to bind to specific enhancer sequences to express genes.
The researchers used single-cell RNA sequencing and single-cell detection transposase-reachable chromatin to determine the enhancer sequence and its corresponding transcription factors through sequencing to play a role
in hair cell regeneration.

Jimenez said: "Our study identified two families of transcription factors that work together to activate hair cell regeneration in zebrafish, known as Sox and Six transcription factors
.
"

First, the Sox transcription factor initiates a regenerative response in surrounding cells, called support cells
.
Next, Sox and Six transcription factors work together to convert these support cells into hair cells
.

When the hair cells of the zebrafish die, nearby support cells begin to replicate
.
These support cells are like stem cells because they have the ability to turn into other types of cells
.
Researchers have identified some of the factors that transform support cells into hair cells, but what is not clear is how and where the genes encoding these factors are activated and coordinated with
other unknown factors.

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

References:

A regulatory network of Sox and Six transcription factors initiate a cell fate transformation during hearing regeneration in adult zebrafish