Key mechanism controlling skin regeneration identified

It’s sunburn time. Many of us have experienced the pain and peeling that comes from unprotected time in the sun, but we may not be paying attention to a notable and important part of the process: the regeneration of the skin as the damaged tissue is replaced with new one.

Even without sunburn, the outer layer of skin, the epidermis, is constantly being remodeled throughout our lives to replace dead or damaged cells. This epidermal layer provides an essential barrier to the human body, reducing water loss and combating environmental hazards. Scientists are working to identify the molecular mechanisms that control skin epidermal regeneration, but much remains poorly understood.

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

“Skin stem cells must constantly make decisions to either make more copies of themselves — a process known as self-renewal — or redirect their fate toward differentiation. A delicate balance between these two decisions is critical to maintaining skin integrity and its barrier function,” said Xiaomin Bao, a stem cell biologist at Northwestern who oversaw the research. “We discovered the switch bound to selected genomic regions within stem cells, ready to trigger the cell fate switch that initiates the stem cell’s movement toward differentiation.”

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

The study was recently published in the journal Nature Communications.

Discovery of the switch

The integrity of the dermal epidermis relies on subsets of dermal stem cells to continuously renew or differentiate themselves to compensate for daily wear and tear. The differentiation process involves significant changes in more than 6,000 genes, stopping stem cell proliferation while activating genes with barrier function.

By integrating genomics, genetics and pharmacological inhibition into human skin models, Bao and her team found that the kinase activity switch of the protein CDK9 plays a key role in the decision of cells to initiate differentiation and gradually take over the tissue barrier function . Kinase activity is turned off in the stem cell state, and the fast-acting genes that are directly controlled by the kinase are suppressed. When kinase activity is turned on, the fast-acting genes are activated, which subsequently induce downstream effectors, a group of transcription factors that can further drive expression of barrier function genes.

CDK9 (cyclin-dependent kinase 9) plays a crucial role in modulating gene expression in the “transcription” step, a process of copying specific regions of DNA into RNA before RNA can serve as a template for the synthesis of new proteins. In the stem cell state, CDK9 is kept in the “off” state when bound on the DNA along with the proteins AFF1 and HEXIM1, awaiting specific cellular signals such as activation of protein kinase C signaling. Once signaling is activated, this is sufficient to switch CDK9 from the inactive to the active state, allowing for the rapid synthesis of RNA from regions of the genome directly bound by CDK9, the researchers found.

The change is quick. “All the components are ready for use deep inside the stem cells,” Bao said. When the stem cell receives certain external signals, the response in the nucleus occurs very quickly, with activated CDK9 rapidly resulting in fast-responding genes such as ATF3 being expressed within just one hour. Expression of ATF3 potently induces multiple downstream transcription factors to rewire cell fate toward differentiation. This fast gene activation switch also relies on the pre-recruitment of the RNA synthesis machinery along with CDK9 to the fast responding genes before signaling is activated.

“We’re investigating the unknown,” Bao said. “Regulation of stem cells is fundamental to maintaining the integrity of human tissues. We have found a key mechanism that initiates the fate change of skin stem cells towards differentiation, an integral regeneration process. Learning more about the basic molecular mechanisms can help to understand many different human diseases.”

Relation: Lloyd SM, Leon DB, Brady MO, et al. CDK9 activity switch associated with AFF1 and HEXIM1 controls differentiation initiation of epidermal progenitors. Nat Commun. 2022;13(1):4408. doi: 10.1038/s41467-022-32098-2

This article was republished from the following materials. Note: The material may have been edited for length and content. For more information, please refer to the given source.