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

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.Electronic supplementary materialThe online version of this article (doi:10.1186/s13148-017-0389-4) contains supplementary material, which is available to authorized users.

Epigenetic signatures of Werner syndrome occur early in life and are distinct from normal epigenetic aging processes

“…The samples with WRN and LMNA mutations clustered together and were distinct from nonmutant patients and controls. A conceptually related study (Guastafierro et al, ) found profound blood methylation differences between three classical WS patients and controls; however, these results were not statistically significant. We now report a more comprehensive methylome analysis of 24 independent patients with segmental progeria (18 with WRN , 3 with LMNA , and three with POLD1 mutations) together with carefully matched controls.…”

PRDM8 exhibits antitumor activities toward hepatocellular carcinoma by targeting NAP1L1

“…It is also possible that HES5 might be an upstream regulator of PRDM8. Aberrant hypermethylation of PRDM8 is observed in dyskeratosis congenital, aplastic anemia, Down syndrome, and Werner syndrome . PRDM8 has hypomethylated CpG islands in endometrial cancer .…”

Scratching the Surface of Werner Syndrome and Human Ageing

“…By analyzing genome-wide DNA methylation profiles of the whole blood from 3 patients with Werner syndrome and 3 age-and sex-matched healthy individuals, hypermethylated sites were enriched for genes involved in glycosphingolipid biosynthesis, FoxO signaling, and insulin signaling pathways, while hypomethylated sites were enriched in PI3K-Akt signaling and focal adhesion pathways [Guastafierro et al, 2017]. Out of 47 differentially methylated genes, 22, belonging to the enriched biochemical pathways, were differentially expressed in Werner syndrome fibroblasts.…”

“…Although systemic sclerosis and dyskeratosis congenita are distinct from the skin lesions in patients with Werner syndrome, the altered methylation patterns of the ITGA9 and ADAM12 genes are intriguing and suggest a link between systemic sclerosis and Werner syndrome. Both the studies of Maierhofer et al [2017] and Guastafierro et al [2017] indicate a novel approach to the pathology of Werner syndrome and general ageing. Further research is needed to elucidate as to how precisely epigenetic changes and possibly altered gene expression patterns in somatic cells may contribute to stochastic age-related pathology in humans in general.…”

“…Recent studies indicated alterations in DNA methylation patterns in blood cells as a possible epigenetic marker of accelerated ageing in Werner syndrome [Guastafierro et al, 2017;Maierhofer et al, 2017]. These studies are based on the assumption that the physiological age of tissues can be assessed by combining the DNA methylation levels of multiple dinucleotide markers (CpGs) [Bocklandt et al, 2011;Garagnani et al, 2012;Hannum et al, 2013;Horvath, 2013;Lin et al, 2016].…”