CDK9 activity switch associated with AFF1 and HEXIM1 controls differentiation initiation from epidermal progenitors

Area of Science:

• Cell Biology
• Developmental Biology
• Molecular Biology

Background:

• Epithelial progenitor cells, like those in human skin, must balance self-renewal and differentiation.
• Understanding the molecular mechanisms governing these fate decisions is crucial for tissue homeostasis and regeneration.

Purpose of the Study:

• To investigate the role of the Super Elongation Complex (SEC) in controlling epithelial progenitor cell fate.
• To identify the molecular targets and mechanisms by which SEC regulates self-renewal versus differentiation.

Main Methods:

• Analysis of paused and elongating RNA Polymerase II (Pol II) in progenitor states.
• Investigating the interaction of SEC with CDK9 and HEXIM1.
• Assessing the impact of SEC modulation (e.g., peptidomimetic inhibitors) on gene expression and differentiation markers.

Main Results:

• SEC directly suppresses a set of
• rapid response
• genes enriched for paused Pol II in progenitors.
• SEC's repressive function relies on the AFF1 scaffold and involves inactive CDK9.
• ATF3 is a key SEC target gene that drives differentiation by upregulating transcription factors like GRHL3 and OVOL1.
• SEC inhibition or PKC signaling rapidly activates CDK9 and induces differentiation transcription factors.

Conclusions:

• The activity switch of SEC-associated CDK9 is a critical determinant of progenitor fate decisions.
• SEC acts as a key regulator, suppressing differentiation pathways to maintain the progenitor state.
• Targeting SEC offers a potential strategy for manipulating epithelial cell differentiation.