Tissue-resident stem cells (SCs) have the capacity togenerate self-assembling organ-like structures, a property that was first demonstrated in cultures of primary human epidermal cells (keratinocytes). There is however marked heterogeneity in the proliferative potential of
individual human keratinocytes. To uncover the molecular mechanisms
underlying this heterogeneity, we performed genome-wide pooled RNAi
screens in normal human keratinocytes (NHKs) and cutaneous squamous
cell carcinoma (cSCC) cells. The Hippo signalling effector YAP was the top
hit amongst positive growth regulators of NHKs, and was also identified as a positive cSCC cell growth regulator. We additionally identified WW-binding protein 2 (WBP2) as an important co-factor that enhances YAP's co-activator functions to drive TEAD transcription factor-mediated gene transcription. YAP and WBP2 were found to be highly expressed in actively proliferating cells of mouse and human epidermis and cSCC. WBP2 deletion in mouse skin resulted in reduced proliferation in wounded adult epidermis. We conclude that YAP, in combination with WBP2 and TEAD transcription factors, drives self-renewal of actively cycling human epidermal SCs to facilitate tissue repair.

A genome-wide screen identifies YAP/WBP2/TEAD interplay conferring growth advantage on human epidermal stem cells.