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Wednesday, November 30, 2022

Key mechanisms controlling skin regeneration identified

It’s sunny weather. Many of us have experienced the pain and peeling that comes from unprotected time in the sun, but we can’t focus on one remarkable and important part of the process: the regeneration of skin in the form of damaged tissue. is replaced with.

Even without sunburns, the outer layer of skin, the epidermis, is constantly changing to replace dead or damaged cells throughout our lifetimes. This epidermal layer provides an essential barrier for the human body, minimizing water loss and combating environmental hazards. Scientists are working to identify the molecular mechanisms controlling epidermal regeneration of the skin, but little is understood.

Now a Northwestern University research team has identified a molecular switch through a protein called CDK9, which plays an early and important role in the skin stem cell differentiation process. This switch is “off” in stem cells. When the switch is turned on, a specific set of genes are immediately activated to trigger downstream gene regulators, allowing skin cells to progressively acquire barrier functions. In addition to a fundamental understanding of skin regeneration, the findings have relevance for a better understanding of cancer and wound healing.

“Skin stem cells constantly need to make decisions, either to make more copies of themselves — a process known as self-renewal — or to change their fates toward differentiation. These two decisions A delicate balance between the skin integrity and its barrier function is important to maintain,” said Xiaomin Bao, a stem cell biologist at Northwestern who supervised the research. “We bound to selected genomic regions inside stem cells. The switch is discovered, which is poised to trigger the cell fate switch to initiate the movement of stem cells towards differentiation.”

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Bao is an assistant professor of molecular biosciences in the Weinberg College of Arts and Sciences and an assistant professor of dermatology at the Northwestern University Feinberg School of Medicine. Her laboratory studies the fundamental biology of the process of skin stem cell differentiation.

The study was recently published by the journal Nature Communications.

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The integrity of the skin’s epidermis depends on a subset of skin stem cells that continually self-renew or differentiate, compensating for daily wear and tear. The differentiation process involves significant alterations from more than 6,000 genes, activating barrier-function genes while inhibiting stem cell proliferation.

Integrating genomics, genetics and pharmacological barrier to human skin models, Bao and his team identified that the kinase activity switch of the protein CDK9 is involved in the decision of cells to initiate differentiation and progressively acquire the barrier function of tissue. plays an important role. In the stem cell stage kinase activity is turned off, and rapid-response genes directly controlled by the kinase are repressed. When kinase activity is turned on, rapid-responder genes are activated, which subsequently induce downstream effectors, a group of transcription factors that can upregulate the expression of barrier-function genes.

CDK9 (cyclin-dependent kinase 9) plays an important role in modulating gene expression at the stage of “transcription”, a process of copying specific DNA regions to RNA, before RNA templates to synthesize new proteins. to work as. In the stem cell state, CDK9 is maintained in the “off” state when proteins on DNA bind with AFF1 and HEXIM1, awaiting specific cellular signals such as activation of protein kinase C signalling. Once the signaling is activated, it is sufficient to switch CDK9 from inactive to active state, allowing rapid synthesis of RNA from genomic regions directly from CDK9, the researchers found.

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The switch is a quick one. “All the components are ready for action deep inside the stem cell,” Bao said. When the stem cell receives specific external signals, the response inside the nucleus is very rapid, with activated CDK9 rapidly responding genes such as ATF3 being expressed within an hour. Expression of ATF3 potentially induces multiple downstream transcription factors to reprogram cell fate toward differentiation. This quick switch to gene activation is also made upon pre-recruitment of the RNA-synthesis machinery with CDK9 to rapid-response genes, before signaling is activated.

“We are investigating the unknown,” Bao said. “Stem cell regulation is fundamental for maintaining the integrity of human tissue. We have found the fate switch of skin stem cells to be a key mechanism leading to differentiation, an integral process of regeneration. About fundamental molecular mechanisms Knowing more could help understand many different human diseases.”

Reference: Lloyd SM, Leon DB, Brady MO, et al. AFF1 and HEXIM1-associated CDK9 activity switches control differentiation initiation from epidermal progenitors. net commune, 2022;13(1):4408. doi: 10.1038/s41467-022-32098-2

This article has been republished from the following materials. Note: Content may have been edited for length and content. For more information, please contact the cited source.

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