SHP-1 promoter 2 methylation in normal epithelial tissues and demethylation in psoriasis

Abstract

SHP-1 promoter hypermethylation has been studied in hematopoietic cells and observed only in various types of lymphoma and leukemia. This study reports a contrasting situation in normal epithelial tissues and an association with skin pathogenesis, particularly in psoriasis. We investigated several cell lines, five of them were epithelial and six were hematopoietic, white blood cells from normal, healthy donors, and normal microdissected epithelium of kidney, liver, breast, cervix, lung, prostate, bladder, and skin. Interestingly, promoter 2 hypermethylation was apparent in all epithelial cell lines and tissues. However, distinctive degrees of demethylation were noted in some skin samples. The methylation patterns of each cell line corresponded to their mRNA isoforms, in that isoforms I and II could not be detected with either promoter 1 or 2 hypermethylation, respectively. We further explored whether an enhanced degree of demethylation could be observed in various dermatopathology lesions. While the promoter 2 methylation levels of squamous cell cancers, eczemas, and normal skins were not different, a significant degree of demethylation can be observed in psoriasis (p<0.005). In addition, psoriasis displays a higher level of SHP-1 isoform II than normal skin (p<0.05). In conclusion, this study discovered an unprecedented role of SHP-1 methylation in tissue-specific expression and its alteration in a nonmalignant human disease besides the transcription inhibition in leukemia and lymphoma. Furthermore, the promoter demethylation may play an important role in skin pathogenesis by enhancing SHP-1 isoform II transcription in psoriatic skin lesions.

IL-6 Modulates CD5 Expression in B Cells from Patients with Lupus by Regulating DNA Methylation

“…Treatment with HpaII confirmed demethylation in two of six SLE patients but in none of the HCs. The positive control was the DNA methylation of Daudi cell line cells (23). The negative control was the HpaII isoschizomer, MpsI, that cut the CpG sequences so that there were no PCR products.…”

The Genetics of Human Skin Disease

“…Similarly, hypomethylation of p16INK4A (antiapoptotic gene) has been reported in psoriasis, along with demethylation of one of the promoters of the SHP-1 gene, important for keratinocyte growth and proliferation (Ruchusatsawat et al 2006;Zhang et al 2007;Chen et al 2008). Importantly, the findings from these studies provides additional evidence that the molecular defects underlying polygenic skin diseases transcend single-gene mutations, and may be characterized by more global changes at the chromatin level associated with a multitude of downstream effects on gene expression.…”

Genome-Wide DNA Methylation Profiling in Diabetogenic and Regulatory T Cells from NOD Mice

“…Based on these genome-wide analyses, our studies have found that Tpaths and Tregs have different methylation density distribution in their autosomes and chromosome X. These novel results suggest epigenetic differences may contribute to the functional differentiation/specification of Tpaths vs. Tregs [29][30][31][32][33][34][35][36][37][38][39][40][41][42][43].…”

“…[37], and p16, SHP1, p15, and p21 in psoriasis [38][39][40]. The overexpression of two methyl CpG -binding domain (MBD) proteins, MBD2 and MBD4, may assoiated with the DNA hypomethylation in SLE CD4 + T cells [41].…”