PDCD5基因调控序列病理性高甲基化的分子机制及其在寻常型银屑病发病中的作用

The mechanisms of psoriasis vulgaris remain unknown, characterized by abnormal keratinocytes proliferation and differentiation. Studies showed that DNA methylation is closed related, with many mysteries to be illuminated. Our previous investigation of genomic DNA methylation status between involved lesions, uninvolved lesions from patients with psoriasis vulgaris and normal skin tissues demonstrated that compared to normal control and non-skin lesions, hypermethylation of gene PDCD5 was observed in psoriatic skin lesions （mechanism unknown）. Correlation analysis showed that methylation levels of gene PDCD5 was positively correlated with patients' PASI scores. mRNA expression of PDCD5 was significantly down-regulated in psoriatic skin lesions. It was reported that IL-23/-17 are important inflammatory mediators in psoriasis, probably regulated by PDCD5. Therefore, based on the previous findings, we assume that DNMTs recruited by unknown TF to gene PDCD5 results in PDCD5 hypermethylation and decreased expression, which leads to increased IL-23/-17 expression, abnormal keratinocytes proliferation and psoriatic lesions. The project will provide further information on the mechanisms of psoriasis vulgaris.

寻常型银屑病发病机制尚不清楚，角质形成细胞过度增殖和异常分化是重要的病理特征；研究表明，DNA甲基化与其密切相关，但机制尚未阐明。本课题组前期对寻常型银屑病皮损组织、非皮损组织及正常皮肤组织进行全基因组DNA甲基化测序（MeDIP-Seq）发现，与正常皮肤组织和非皮损区组织相比，基因PDCD5在寻常型银屑病皮损区呈高甲基化状态（原因不明），且甲基化状态和患者PASI评分正相关；皮损组织中PDCD5 mRNA表达水平亦显著降低。文献报道称，IL-23/-17是寻常型银屑病中重要的炎症介质，且可能受到基因PDCD5的负调控。因此，我们提出如下假说：DNA甲基转移酶在某转录因子的招募下作用于基因PDCD5→基因PDCD5调控序列发生高甲基化→PDCD5表达下调→IL-23/-17表达增高→角质形成细胞过度增殖和异常分化→形成银屑病的特征性皮损。本项目将有助于进一步阐明寻常型银屑病的发病机制。