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.
Highlights
Keratinocyte differentiation requires expression of genes clustered in chromosome 1q21, collectively referred to as epidermal differentiation complex (EDC)
Among the genes differentially expressed by Grainyhead-like 2 (GRHL2) transduction, the genes that belong to EDC, for example, IVL, FLG, late cornifying envelope (LCE), and small proline-rich (SPRR), were consistently downregulated in normal human epidermal keratinocytes (NHEK)/GRHL2 compared with the controls
Microarray data were validated by quantitative reverse transcription–PCR, which confirmed suppression of the EDC genes in NHEK/GRHL2 compared with the control (Figures 1b and c)
Summary
Keratinocyte differentiation requires expression of genes clustered in chromosome 1q21, collectively referred to as epidermal differentiation complex (EDC). Defective expression or mutation of EDC genes is linked with various skin disorders, in part, from impaired epidermal barrier. Received 15.8.12; revised 28.9.12; accepted 30.10.12; Edited by E Candi transcriptase) gene and enhances replicative potential of normal human epidermal keratinocytes (NHEK).[17] In the current study, we show that GRHL2 inhibits keratinocyte differentiation through epigenetic suppression of EDC gene expression. Immunohistochemical staining of GRHL2 and gene expression analyses showed increased GRHL2 expression in epidermal tissues exhibiting AD or PS histopathology compared with normal skin. These lesions demonstrated hyperproliferative epithelium and impaired EDC gene expression, suggesting potential involvement of GRHL2 in epithelial pathology of skin
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