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

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.

The AP-1 transcription factor component Fosl2 potentiates the rate of myocardial differentiation from the zebrafish second heart field

“…This would significantly reduce the number of SHF progenitors capable of producing the full complement of ventricular cardiomyocytes. Although this model is consistent with the reported sufficiency of Fosl2 to increase the differentiation of osteoblasts (Bozec et al, 2010) and drive precocious differentiation of keratinocytes (Wurm et al, 2015), we cannot rule out other cellular mechanisms that might explain the overexpression phenotype.…”

“…Although several transcriptional targets have been identified for Fosl2 (Bozec et al, 2010(Bozec et al, , 2008Luther et al, 2014) and crucial regulators of SHF differentiation have been described (Rochais et al, 2009), we are not aware of any genes that fit into both categories. With regard to cellular differentiation, Fosl2 transcriptionally activates osteocalcin (Bozec et al, 2010) and members of the epidermal differentiation complex (Wurm et al, 2015) to positively regulate osteoclast and epidermal differentiation, respectively. However, because of the lineage restricted and non-cardiac nature of these particular targets, they are unlikely to mediate the role of Fosl2 in heart development.…”

Confluence-Induced Squamous Differentiation Is Not Accompanied by Changes in H3K27me3 Repressive Epigenetic Mark

“…Although the molecular basis for noncontextual H3K27me3-dependent differentiation events is unclear, it is interesting to speculate that it may involve nonhistone methylation events. For example, a recent report described a role for EZH2 in the context of squamous differentiation (Wurm et al, 2015). Specifically, it was reported that, in murine keratinocytes, EZH2 directly methylates the transcription factor Fra-2, an activator protein-1 family member, resulting in inhibition of its transcriptional activity yet continued binding to promoter elements (Wurm et al, 2015).…”

“…Adding to this complexity, it has been shown that transition from a neonatal state to an adult state is accompanied by a loss of expression of EZH2 and an increase in EZH1 in murine skin (Ezhkova et al, 2009). A recent study has also suggested that EZH2 is able to methylate the transcription factor activator protein-2 and thereby influence transcription of differentiation genes in murine epidermis (Wurm et al, 2015). Hence, the role of PRC-2-mediated gene regulation in squamous differentiation remains unclear.…”

“…The growth arrest, which precedes terminal differentiation, is irreversible and characterized by the decreased expression of proliferationassociated genes such as CDC2 and E2F1 Dahler et al, 1998;Dicker et al, 2000), followed by the induction of differentiation-associated genes such as keratin-10, involucrin (IVL), and transglutaminase 1 (Fuchs and Green, 1980;Eckert, 1989). Although the expression of differentiation-specific genes is largely regulated by transcription factors (Eckert et al, 1997), there is recent evidence that epigenetic mechanisms (Sen et al, 2008(Sen et al, , 2010Ezhkova et al, 2009;Shaw and Martin, 2009;Wurm et al, 2015) may regulate this transcriptional program. In particular, the repressive histone modification, histone H3 lysine 27 trimethylation (H3K27me3), has been reported to repress differentiation genes in proliferative and undifferentiated keratinocytes in epidermal development (Ezhkova et al, 2009), in a wound healing model (Shaw and Martin, 2009), and in undifferentiated adult keratinocytes in vitro (Sen et al, 2008).…”