Genome-wide DNA methylation analysis in blood cells from patients with Werner syndrome.

T Guastafierro,A Spanò,P Garagnani,C Franceschi,A Marcoccia,D Raimondo,S Pisoni,D Gentilini,F Bondanini,A M Di Blasio,A Corsi,M G Bacalini

doi:10.1186/s13148-017-0389-4

Abstract

BackgroundWerner 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.ResultsTo 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 CERS1 and CERS3, two members of the ceramide synthase family. Moreover, we found differentially methylated probes within ITGA9 and ADAM12 genes, whose methylation is altered in systemic sclerosis, and within the PRDM8 gene, whose methylation is affected in dyskeratosis congenita and Down syndrome.ConclusionsDNA 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.

Highlights

Werner syndrome (WS) is a rare adult premature ageing disease
We found 27 differentially methylated regions (DMRs) with a non-adjusted P value < 0.001 (Additional file 3, Additional file 4, Table 3), 20 of which were clearly hypermethylated in WS patients compared to CTRs
In summary, we identified for the first time genome-wide DNA methylation changes in the peripheral blood from WS patients, providing important new insight in the pathogenesis of the diseases and emphasizing the potential role of DNA methylation changes in Werner disorder

Summary

Introduction

Individuals affected by WS generally have a normal development until the third decade of life, when premature ageing phenotypes and symptoms begin to manifest including premature greying or loss of hair, birdlike faces, cataracts, sclerodermiform skin atrophy [1] and WS represents an important part of the differential diagnosis in patients who present with scleroderma-like skin changes, as they share with SSc patients the main histological changes of skin. WRN protein is crucial in maintaining genome structure and integrity, and WS patients exhibit early age-associated biomarkers like DNA damage accumulation and chromosomal instability [14]. Despite these evidences, the molecular bases of WS phenotype are still largely unknown. 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

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Discussion

Conclusion