UOC of Clinical Biochemistry, Sandro Pertini Hospital, Rome, Italy.
CRIIS (Interdisciplinary, Interdepartmental and Specialistic Reference Center for Early Diagnosis of Scleroderma, Treatment of Sclerodermic Ulcers and Videocapillaroscopy), Sandro Pertini Hospital, Rome, Italy.
Clin Epigenetics. 2017 Aug 30;9:92. doi: 10.1186/s13148-017-0389-4. eCollection 2017.
Werner syndrome is a progeroid disorder characterized by premature age-related phenotypes. Although it is well established that autosomal recessive mutations in the WRN gene is responsible for Werner syndrome, the molecular alterations that lead to disease phenotype remain still unidentified.
To address whether epigenetic changes can be associated with Werner syndrome phenotype, we analysed genome-wide DNA methylation profile using the Infinium MethylationEPIC BeadChip in the whole blood from three patients affected by Werner syndrome compared with three age- and sex-matched healthy controls. Hypermethylated probes were enriched in glycosphingolipid biosynthesis, FoxO signalling and insulin signalling pathways, while hypomethylated probes were enriched in PI3K-Akt signalling and focal adhesion pathways. Twenty-two out of 47 of the differentially methylated genes belonging to the enriched pathways resulted differentially expressed in a publicly available dataset on Werner syndrome fibroblasts. Interestingly, differentially methylated regions identified and , two members of the ceramide synthase family. Moreover, we found differentially methylated probes within and genes, whose methylation is altered in systemic sclerosis, and within the gene, whose methylation is affected in dyskeratosis congenita and Down syndrome.
DNA methylation changes in the peripheral blood from Werner syndrome patients provide new insight in the pathogenesis of the disease, highlighting in some cases a functional correlation of gene expression and methylation status.
Werner 综合征是一种早老性疾病，其特征为过早出现与年龄相关的表型。虽然已经确定，WRN 基因的常染色体隐性突变是 Werner 综合征的原因，但导致疾病表型的分子改变仍然未知。
为了研究表观遗传变化是否与 Werner 综合征表型有关，我们使用 Infinium MethylationEPIC BeadChip 在来自三位 Werner 综合征患者的全血中分析了全基因组 DNA 甲基化图谱，与三位年龄和性别匹配的健康对照进行了比较。超甲基化探针在糖脂生物合成、FoxO 信号和胰岛素信号通路中富集，而低甲基化探针在 PI3K-Akt 信号和焦点黏附通路中富集。在 Werner 综合征成纤维细胞的公开数据集上，属于富集通路的 47 个差异甲基化基因中有 22 个表现出差异表达。有趣的是，鉴定出的差异甲基化区域 和 ，这两个基因都属于神经酰胺合酶家族。此外，我们还在 和 基因内发现了差异甲基化探针，这两个基因在系统性硬化症中甲基化改变，在 基因内发现了差异甲基化探针，该基因在先天性角化不良和唐氏综合征中甲基化受到影响。
Werner 综合征患者外周血中的 DNA 甲基化变化为疾病的发病机制提供了新的见解，突出了某些情况下基因表达和甲基化状态之间的功能相关性。
