Scientists identify key mechanism controlling skin regeneration
The outer layer of skin, the epidermis, is constantly turning over to replace dead or damaged cells throughout our lifetime. This epidermal layer provides an essential barrier for the human body, reducing water loss and combating environmental threats. Scientists are working to identify the molecular mechanisms controlling skin epidermal regeneration, but much remains poorly understood.
Now a Northwestern University research team has identified a molecular switch, through a protein called CDK9, that plays an early and critical role in the skin stem cell differentiation process. This switch is “off” in the stem cells. When the switch is turned on, a specific group of genes is immediately activated to trigger downstream gene regulators, allowing the skin cells to progressively gain barrier function. The findings have relevance for improved understanding of cancer and wound healing, in addition to the fundamental understanding of skin regeneration.
The integrity of skin epidermis relies on subsets of skin stem cells to continuously self-renew or differentiate, compensating for daily wear and tear. The differentiation process involves significant changes from more than 6,000 genes, ceasing stem cell proliferation while activating barrier-function genes.
Integrating genomics, genetics and pharmacological inhibition to human skin models, Bao and her team identified that the kinase activity switch of the protein CDK9 plays a key role in the decision of cells to initiate differentiation and progressively acquire the barrier function of the tissue. The kinase activity is off in the stem cell state, and the rapid-response genes directly controlled by the kinase are suppressed. When the kinase activity is on, the rapid-response genes are activated, which subsequently induce the downstream effectors, a group of transcription factors that can further drive the expression of barrier-function genes.
CDK9 (cyclin-dependent kinase 9) plays crucial roles in modulating gene expression at the step of “transcription”. In the stem cell state, CDK9 is maintained in the “off” state when bound together with the proteins AFF1 and HEXIM1 on DNA, awaiting specific cellular signals such as the activation of protein kinase C signaling. Once the signaling is activated, this is sufficient to switch CDK9 from the inactive to the active state, allowing the rapid synthesis of RNA from the genomic regions directly bound by CDK9, the researchers found.
When the stem cell receives specific external signals, the response inside the nucleus is very fast, with activated CDK9 quickly causing rapid-response genes such as ATF3 to be expressed within as short as one hour. The expression of ATF3 potently induces several downstream transcription factors to rewire the cell fate towards differentiation.
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