Terminal epidermal differentiation is regulated by the interaction of Fra-2/AP-1 with Ezh2 and ERK1/2

Stefanie Wurm; Jisheng Zhang; Juan Guinea-Viniegra; Fernando García; Javier Muñoz; Latifa Bakiri; Elena Ezhkova; Erwin F. Wagner

doi:10.1101/gad.249748.114

Terminal epidermal differentiation is regulated by the interaction of Fra-2/AP-1 with Ezh2 and ERK1/2

¹BBVA Foundation–CNIO Cancer Cell Biology Program, Spanish National Cancer Research Centre (CNIO), Madrid E28029, Spain;
²Medical Research Center, The Affiliated Hospital of Qingdao University, Qingdao, Shandong Province 266500, China;
³Proteomics Unit, Spanish National Cancer Research Centre (CNIO), Madrid E28029, Spain;
⁴Developmental and Regenerative Biology, Black Family Stem Cell Institute, Mount Sinai School of Medicine, New York, New York 10029, USA

Corresponding author: ewagner{at}cnio.es

Abstract

Altered epidermal differentiation characterizes numerous skin diseases affecting >25% of the human population. Here we identified Fra-2/AP-1 as a key regulator of terminal epidermal differentiation. Epithelial-restricted, ectopic expression of Fra-2 induced expression of epidermal differentiation genes located within the epidermal differentiation complex (EDC). Moreover, in a papilloma-prone background, a reduced tumor burden was observed due to precocious keratinocyte differentiation by Fra-2 expression. Importantly, loss of Fra-2 in suprabasal keratinocytes is sufficient to cause skin barrier defects due to reduced expression of differentiation genes. Mechanistically, Fra-2 binds and transcriptionally regulates EDC gene promoters, which are co-occupied by the transcriptional repressor Ezh2. Fra-2 remains transcriptionally inactive in nondifferentiated keratinocytes, where it was found monomethylated and dimethylated on Lys104 and interacted with Ezh2. Upon keratinocyte differentiation, Fra-2 is C-terminally phosphorylated on Ser320 and Thr322 by ERK1/2, leading to transcriptional activation. Thus, the induction of epidermal differentiation by Fra-2 is controlled by a dual mechanism involving Ezh2-dependent methylation and activation by ERK1/2-dependent phosphorylation.

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Supplemental material is available for this article.
Article published online ahead of print. Article and publication date are online at http://www.genesdev.org/cgi/doi/10.1101/gad.249748.114.

Received July 28, 2014.
Accepted December 2, 2014.

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