GSE184767
Detection of genome-wide methylation changes in prion-infected central nervous system
Scrapie is a Transmissible Spongiform Encephalopathy (TSE) that affects sheep and goats and it is considered a good natural animal model to study prion diseases. Although changes in DNA methylation occur in many neurodegenerative diseases including human prion diseases, potential DNA methylation alterations have not yet been investigated in the central nervous system (CNS) of any prion disease models or naturally infected cases. We present here a whole genome bisulfite sequencing analysis (WGBS) from thalamus of four naturally scrapie infected sheep and four controls. All animals were female, carried the ARQ/ARQ genotype for the PRNP allele and were sacrificed at similar age (4 to 6 years old). Even if genomes displayed similar average methylation levels, we identified 39 differentially methylated promoters (DMP) and a total of 8,907 differentially methylated regions (DMR). Gene Ontology enrichment revealed that hypomethylated DMRs were enriched in genes involved in transmembrane transport and cell adhesion whereas hypermethylated DMRs were related with intracellular signal transduction genes. Moreover, we compared the set of identified DMRs with genes previously described to be differentially expressed in scrapie and with a set of genes encoding proteins defined to be tenfold more abundant in specific types of CNS cells finding that some of these genes also harboured DMRs. Finally, a validation study using qPCR was conducted showing differences in the expression of five genes (PCDH19, SNCG, WDR45B, PEX1 and CABIN1) that matched the methylation changes observed in the genomic study. Altogether, these findings suggest a potential regulatory role of CNS DNA methylation in prion diseases. Overall design: DNA methylation profiling using whole-genome bisulfite sequencing of 8 sheep thalamus samples, 4 samples from control sheep and 4 samples from sheep naturally infected with scrapie.