407 Epigenetic control of epithelial stem cell differentiation by Galpha-s and protein kinase A signaling

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We have recently demonstrated in mice that conditional epidermal deletion of the gene coding for the Galpha-s subunit (Gnas) or inactivation of the Galpha-s signaling partner protein kinase A (PKA) are alone sufficient to cause an aberrant expansion of the stem cell compartment, resulting in the rapid formation of basal cell carcinoma-like lesions (Iglesias-Bartolome et al, Nature Cell Biology, 17:p793, 2015). In order to investigate how Galpha-s and PKA signaling affect long term epigenetic events that regulate epithelial stem cell differentiation, we focused on EZH2, a master epigenetic regulator. EZH2 is part of the polycomb repressor complex and is responsible for gene silencing of differentiation genes in keratinocytes by the trimethylation of histone 3 lysine 27 (H3K27me3). We found that in mice, conditional epidermal deletion of Galpha-s causes an upregulation of the levels of EZH2 protein. Furthermore, bioinformatic analysis of gene expression in these mice revealed transcriptional signatures related to activation of EZH2. In the search for potential mechanisms underlying the impact of Galpha-s on EZH2, we focused on PKA, one of the main Galpha-s signaling partners. By performing kinase assays in vitro, we observed that PKA can directly phosphorylate EZH2. By mutational analysis and by measuring the enzymatic activity and association with other epigenetic components, we are currently dissecting the mechanisms and significance of EZH2 regulation by Galpha-s and PKA.