ZNF750 Is a p63 Target Gene that Induces KLF4 to Drive Terminal Epidermal Differentiation

Abstract

SUMMARY Disrupted epidermal differentiation characterizes numerous diseases that impact >25% of the population. In a search for dominant mediators of differentiation, we defined a requirement for ZNF750 in terminal epidermal differentiation. ZNF750 controlled genes mutated in numerous human skin diseases, including FLG, LOR, LCE3B, ALOXE3, and SPINK5. ZNF750 induced progenitor differentiation via an evolutionarily conserved C2H2 zinc finger motif. The epidermal master regulator, p63, bound the ZNF750 promoter and was necessary for its induction. ZNF750 restored differentiation to p63-deficient tissue, suggesting it acts downstream of p63. A search for functionally important ZNF750 targets via analysis of ZNF750-regulated genes identified KLF4, a transcription factor that activates late epidermal differentiation. ZNF750 binds to KLF4 at multiple sites flanking the transcriptional start site and controls its expression. ZNF750 thus directly links a tissue-specifying factor, p63, to an effector of terminal differentiation, KLF4, and represents a potential future target for disorders of this process.

p53/p63/p73 in the Epidermis in Health and Disease

“…(AP-2g, IKK-a, IRF6, HBP1, Runx1, ZNF750), and DNA repair machinery (BRACA2, MRE11, Rad51) (Koster et al 2004;Ihrie et al 2005;Koster and Roop 2007;Lin et al, 2009;Shalom-Feuerstein et al 2011;Vanbokhoven et al 2011;Sen et al 2012). p63 transcriptional activity is also regulated and inhibited by the FoxO transcription factor, which directly binds to p63 protein and prevents its interaction with gene promoters.…”

GRHL2 coordinates regeneration of a polarized mucociliary epithelium from basal stem cells

“…Significantly, we also show that Grhl2 positively regulates genes associated with progenitor cell differentiation and lineage choice. These include multiple Notch pathway and ciliogenesis genes and the transcription factor Znf750, which has recently been implicated in driving epidermal keratinocyte differentiation (Sen et al, 2012;Boxer et al, 2014). Collectively, our findings establish a role for Grhl2 as a key integrator of epithelial morphogenesis and differentiation in multiple vertebrate organ systems.…”

“…For further studies, we focused on SMA GP (encoding a small transmembrane and glycosylated protein; Tarbé et al, 2004) and ZNF750 (also known as zinc finger protein 750, or Zfp750; encoding a member of the C2H2 subclass of zinc finger transcription factors; Birnbaum et al, 2006;Cohen et al, 2012;Sen et al, 2012;Boxer et al, 2014). As summarized in Fig.…”

Clinical significance of ZNF750 gene expression, a novel tumor suppressor gene, in esophageal squamous cell carcinoma

“…Previously, it was suggested that ZNF750 function was associated with epithelial differentiation (5)(6)(7)10,11). These data suggested that a low expression of ZNF750 is associated with tumor aggressiveness in ESCC.…”

“…However, previous cohorts used to investigate the genomic abnormalities of ESCC were too small to encompass the full range of genomic abnormalities (3,4). The present authors have recently performed whole-exome sequence (WES) analysis on 144 Japanese patients with ESCC, and identified a previously uncharacterized mutant gene, zinc finger protein 750 (ZNF750) (1), which is an essential regulator of epithelial proliferation and differentiation (5)(6)(7).…”