The characteristics of genome-wide DNA methylation in naïve CD4+ T cells of patients with psoriasis or atopic dermatitis

Abstract

Psoriasis and atopic dermatitis (AD) are skin diseases that are characterized by polarized CD4+ T cell responses. During the polarization of naïve CD4+ T cells, DNA methylation plays an important role in the regulation of gene transcription. In this study, we profiled the genome-wide DNA methylation status of naïve CD4+ T cells in patients with psoriasis or AD and healthy controls using a ChIP-seq method. Only psoriasis patient T cells, not those of AD patients, showed distinct hypomethylation (>4-fold) compared to healthy control T cells in twenty-six regions of the genome ranging in size from 10 to 70 kb. These regions were mostly pericentromeric on 10 different chromosomes and incidentally coincided with various strong epigenomic signals, such as histone modifications and transcription factor binding sites, that had been observed in the ENCODE project implying the potential epigenetic regulation in psoriasis development. The gene-centric analysis indicated that the promoter regions of 121 genes on the X chromosome had dramatically elevated methylation levels in psoriasis patient T-cells compared to those from healthy controls (>4-fold). Moreover, immune-related genes on the X chromosome had higher hypermethylation than other genes (P = 0.046). No such patterns were observed with AD patient T cells. These findings imply that methylation changes in naïve CD4+ T cells may affect CD4+ T cell polarization, especially in the pathogenesis of psoriasis.

Introduction

Psoriasis and atopic dermatitis (AD) are common inflammatory skin diseases associated with CD4+ T cell polarization [1], [2]. CD4+ T cells arise from naïve CD4+ T cells. However, naïve CD4+ T cells in psoriasis mainly differentiate into T helper type 1 (Th1) cells in response to Th1 cytokines such as interferon (IFN)-γ [1]. In contrast, AD is predominantly a Th2-polarized disease involving Th2 cytokines such as interleukin (IL)-4 and IL-5 [2]. Immune responses related to T cell polarization are regulated by epigenetic changes [3], [4]. These epigenetic changes may be involved in various skin diseases, including systemic lupus erythematosus and vitiligo [5], [6], [7]. However, the epigenetic changes of naïve CD4+ T cells during psoriasis and AD are not yet fully understood.

Epigenetic regulation of gene expression is a dynamic process in which DNA methylation is a primary mechanism [8]. In mammals, methylation occurs predominantly on CpG dinucleotides that are sparsely distributed within the genome. CpG methylation regulates and stabilizes chromatin structure and controls the recruitment of transcriptional machinery [9]. In general, regulation of CpG methylation is established and maintained by DNA methyltransferases [9]. Karen et al. demonstrated that the expression of Th2 cytokines, such as IL-4, was regulated by DNA methyltransferase-1 in CD4+ T cells [10]. Based on findings from a previous study, proper maintenance of DNA methylation may be critical for the polarization of CD4+ T cells and the development of diseases such as psoriasis and AD. Because psoriasis and AD are associated with improper immune responses, such as imbalanced CD4+ T cell populations, fine-tuning T cell heritage may be important for managing these two diseases [1], [2]. With this hypothesis, we investigated whether DNA methylation in naïve CD4+ T cells is associated with the development of psoriasis and AD.

Here, we describe the genome-wide profile of methylation changes in naïve CD4+ T cells from patients with psoriasis or AD as compared with those of healthy controls. First, we surveyed the global changes along the chromosomes irrespective of gene loci, and found many regions that underwent hypomethylation in patients with psoriasis, not AD. The gene-centric analysis comparing the methylation changes of both promoter and gene-body regions indicated that gene promoter regions on the X chromosome were dramatically hypermethylated in patients with psoriasis. No such patterns were observed with AD patient T cells. Our findings indicate that methylation changes in naïve CD4+ T cells may have important roles during CD4+ T cell polarization, especially in the pathogenesis of psoriasis. Further study of CD4+ T cell polarization based on changes in DNA methylation is necessary to understand the development of psoriasis and AD.