Psoriasis and atopic dermatitis (AD) are skin diseases that are characterized by polarized CD4+ T cell responses. During the polarization of naive 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 naive 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 naive CD4+ T cells may affect CD4+ T cell polarization, especially in the pathogenesis of psoriasis. (C) 2012 Elsevier Inc. All rights reserved.