ZNF750 interacts with KLF4 and RCOR1, KDM1A, and CTBP1/2 chromatin regulators to repress epidermal progenitor genes and induce differentiation genes

Abstract

ZNF750 controls epithelial homeostasis by inhibiting progenitor genes while inducing differentiation genes, a role underscored by pathogenic ZNF750 mutations in cancer and psoriasis. How ZNF750 accomplishes these dual gene regulatory impacts is unknown. Here, we characterized ZNF750 as a transcription factor that binds both the progenitor and differentiation genes that it controls at a CCNNAGGC DNA motif. ZNF750 interacts with the pluripotency transcription factor KLF4 and chromatin regulators RCOR1, KDM1A, and CTBP1/2 through conserved PLNLS sequences. ChIP-seq (chromatin immunoprecipitation [ChIP] followed by high-throughput sequencing) and gene depletion revealed that KLF4 colocalizes~10 base pairs from ZNF750 at differentiation target genes to facilitate their activation but is unnecessary for ZNF750-mediated progenitor gene repression. In contrast, KDM1A colocalizes with ZNF750 at progenitor genes and facilitates their repression but is unnecessary for ZNF750-driven differentiation. ZNF750 thus controls differentiation in concert with RCOR1 and CTBP1/2 by acting with either KDM1A to repress progenitor genes or KLF4 to induce differentiation genes.

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.…”

“…7 D). Expression of ZNF750 protein has been reported in several epithelial tissues including the suprabasal (but not basal) cells of the epidermis (Boxer et al, 2014). However, there is no study of expression in airway mucociliary epithelium.…”

“…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).…”