C/EBPα and β couple interfollicular keratinocyte proliferation arrest to commitment and terminal differentiation

The transcriptional regulators that couple keratinocyte proliferation arrest with commitment to differentiation are yet to be identified. C/EBPs are shown to couple mice basal keratinocyte cell-cycle exit with commitment to differentiation through, respectively, E2F repression and DNA binding. The transcriptional regulators that couple interfollicular basal keratinocyte proliferation arrest to commitment and differentiation are yet to be identified. Here we report that the basic region leucine zipper transcription factors C/EBPα and C/EBPβ are co-expressed in basal keratinocytes, and are coordinately upregulated as keratinocytes exit the basal layer and undergo terminal differentiation. Mice lacking both C/EBPα and β in the epidermis showed increased proliferation of basal keratinocytes and impaired commitment to differentiation. This led to ectopic expression of keratin 14 (K14) and ΔNp63 in suprabasal cells, decreased expression of spinous and granular layer proteins, parakeratosis and defective epidermal water barrier function. Knock-in mutagenesis revealed that C/EBP-E2F interaction was required for control of interfollicular epidermis (IFE) keratinocyte proliferation, but not for induction of spinous and granular layer markers, whereas C/EBP DNA binding was required for ΔNp63 downregulation and K1/K10 induction. Finally, loss of C/EBPα/β induced stem cell gene expression signatures in the epidermis. C/EBPs, therefore, couple basal keratinocyte cell cycle exit to commitment to differentiation through E2F repression and DNA binding, respectively, and may act to restrict the epidermal stem cell compartment.