Correlation between Reversal of DNA Methylation and Clinical Symptoms in Psoriatic Epidermis Following Narrow-Band UVB Phototherapy

Abstract

Epigenetic modifications by DNA methylation are associated with a wide range of diseases. Previous studies in psoriasis have concentrated on epigenetic changes in immune cells or in total skin biopsies that include stromal-associated changes. In order to improve our understanding of the role of DNA methylation in psoriasis, we sought to obtain a comprehensive DNA methylation signature specific for the epidermal component of psoriasis and to analyze methylation changes during therapy. Genome-wide DNA methylation profiling of epidermal cells from 12 patients undergoing narrow-band UVB phototherapy and 12 corresponding healthy controls revealed a distinct DNA methylation pattern in psoriasis compared with controls. A total of 3,665 methylation variable positions (MVPs) were identified with an overall hypomethylation in psoriasis patient samples. DNA methylation pattern was reversed at the end of phototherapy in patients showing excellent clinical improvement. Only 7% of phototherapy-affected MVPs (150 out of 2,108) correlate with nearby gene expression. Enrichment of MVPs in enhancers indicates tissue-specific modulation of the transcriptional regulatory machinery in psoriasis. Our study identified key epigenetic events associated with psoriasis pathogenesis and helps understand the dynamic DNA methylation landscape in the human genome.

Figure 1

Identification of differences in DNA methylation between psoriasis and controls. Scatter plot between methylation changes (delta-beta, psoriasis PRE-UV vs. controls) and corresponding −log₁₀(false-discovery rate (FDR) adj. P-value) for total assessed 470,903 sites was shown. CpG sites with delta-beta>0.2 and −log₁₀(FDR adj. P-value)>2 were defined as methylation variable positions (MVPs). The upper square indicates hypermethylated MVPs, and the bottom square indicates hypomethylated MVPs in psoriasis compared with controls.

Figure 2

Distribution of psoriasis methylation variable positions (MVPs) across genomic regions and related to CpG density. (a) Total accessed CpG sites (470,903) were divided into 16 groups according to genomic location (promoter region, gene body, 3′-UTR or IGR) and CpG density (island, shore, shelf, none). The promoter region refers to TSS1,500, TSS200, 5′-UTR, and 1stExon. MVP percentage in each group is shown in the bar graph. Count of MVPs in each group is also shown in the bottom. (b) Overall hypomethylation in psoriasis. Total MVPs (3,665) were divided into four groups based on genomic location or CpG density. Box plots showed the distribution of beta-value for corresponding MVPs in each group. White boxes represent controls, and gray boxes represent psoriasis (PRE-UV samples).

Figure 3

Score plot from PCA analysis for 12 psoriasis patients undergoing phototherapy and 12 corresponding controls. PCA score plot of the two first PCs of the methylation data set providing a map of how the samples relate to each other. The samples are colored by the sample group. Assessment of clinical response was given in three grades: Excellent, good, or unsatisfactory. POST-UV samples from patients with good or unsatisfactory response to phototherapy are indicated with symbol * or ^#, respectively.