The outer layer of skin, the epidermis, is constantly turning over to replace dead or damaged cells throughout our lifetime. Skin stem cells need to continuously make decisions: either make more copies of themselves (self-renewal) or switch their fate towards differentiation. The gene regulatory mechanisms governing these two distinct progenitor fate choices, especially the early events that initiate the terminal differentiation process, remain incompletely understood.
Skin epidermis, composed of 90% keratinocytes, is a type of highly accessible self-renewing somatic tissue. Multiple signaling pathways including calcium as well as Protein Kinase C (PKC) signaling are closely linked to the activation of keratinocyte differentiation. RNA Polymerase II (Pol II) pause release has emerged as an evolutionarily conserved mechanism for rapidly activating gene expression.
The CDK9 kinase plays a central role in regulating Pol II pause release. The kinase activity of CDK9 is strictly regulated through incorporation into distinct complexes to prevent promiscuous gene induction.
New study findings…
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.
Xiaomin Bao, assistant professor of molecular biosciences in the Weinberg College of Arts and Sciences and an assistant professor of dermatology at Northwestern University Feinberg School of Medicine 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,” a process of copying specific DNA regions to RNA, before RNA can serve as templates for synthesizing new proteins. 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.
With this observation in the study, we are more close to knowing the unknown of the cellular differentiation. Now we understand a little more of the mechanism that activates the initiation of skin stem cell differentiation, taking an integral process of regeneration.
Sarah M. Lloyd, Daniel B. Leon, Mari O. Brady, Deborah Rodriguez, Madison P. McReynolds, Junghun Kweon, Amy E. Neely, Laura A. Blumensaadt, Patric J. Ho, Xiaomin Bao (July 29, 2022). CDK9 activity switch associated with AFF1 and HEXIM1 controls differentiation initiation from epidermal progenitors. Nature. Retrieved from : https://www.nature.com/articles/s41467-022-32098-2
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