Grainyhead-like 2 (GRHL2) inhibits keratinocyte differentiation through epigenetic mechanism

Abstract

We recently identified Grainyhead-like 2 (GRHL2), a mammalian homolog of Grainyhead in Drosophila, to be a novel transcription factor that regulates hTERT gene expression and enhances proliferation of normal human epidermal keratinocytes (NHEK). In the current study, we show that GRHL2 impairs keratinocyte differentiation through transcriptional inhibition of the genes clustered at the epidermal differentiation complex (EDC), located at chromosome 1q21. Gene expression profiling and subsequent in vitro assays revealed consistent downregulation of EDC genes, for example, IVL, KRT1, FLG, LCEs, and SPRRs, in NHEK expressing exogenous GRHL2. In vivo binding assay by chromatin immunoprecipitation revealed GRHL2 association at the promoter regions of its target genes, many of which belong to EDC. Exogenous GRHL2 expression also inhibited recruitment of histone demethylase Jmjd3 to the EDC gene promoters and enhanced the level of histone 3 Lys 27 trimethylation enrichment at these promoters. Survey of GRHL2 expression in human skin tissues demonstrated enhanced protein and mRNA levels in chronic skin lesions with impaired keratinocyte differentiation, for example, atopic dermatitis and psoriasis, compared with normal epidermis. These data indicate that GRHL2 impairs epidermal differentiation by inhibiting EDC gene expression through epigenetic mechanisms and support its role in the hyperproliferative skin diseases.

Grainyhead-like 2 (GRHL2) distribution reveals novel pathophysiological differences between human idiopathic pulmonary fibrosis and mouse models of pulmonary fibrosis

“…We further showed that Grhl2 knockdown in the alveolar type II-like MLE15 cell line resulted in cell-flattening events, with alteration in distribution of F-actin filaments. Moreover, we also suggested that the expression of Tert, which is an important injury repair gene, may be regulated by Grhl2 in alveolar epithelium, which corroborates another study showing that GRHL2 mediates epigenetic regulation of TERT in human keratinocytes (5,6,19). The fact that mutation in TERT is known to predispose to familial IPF (1,22,38) suggests a possible functional role of GRHL2 in the pathogenesis of IPF.…”

Integrative Bioinformatics Analysis Reveals New Prognostic Biomarkers of Clear Cell Renal Cell Carcinoma

“…GRHL2 is a transcription factor playing roles in development, regulation of epithelial mesenchymal transition (EMT), and restoring the sensitivity to anoikis (27 ). GRHL2 overexpression was detected in several cancers; however, in certain subclasses of breast cancer, GRHL2 was downregulated (27,28 ). This dual, context-dependent effect of GRHL2 might be explained by operation through transforming growth factor ␤ (TGF-␤) signaling, which also has both tumorpromoting and -suppressing effects in a contextdependent manner.…”

Grainyhead-like 2 downstream targets act to suppress EMT during neural tube closure

“…GRHL2 directly regulates genes that are essential for epithelial fate, such as those encoding E-cadherin (cadherin 1), claudin 3 and claudin 4 (Mostov et al, 2012;Werth et al, 2010), and other epithelial genes are downregulated in Grhl2 loss-of-function embryos (Pyrgaki et al, 2011). Despite the knowledge of these and other (Chen et al, 2012;Gao et al, 2013;Walentin et al, 2015) GRHL2-regulated downstream processes, it remains to be determined how Grhl2 loss in the NNE leads to failure of NTC. Thus, continuing studies of GRHL2 function could shed light on the molecular processes that underlie NNE-driven NTC.…”