title: Genome-wide profiling of methylation identifies novel targets with aberrant hypermethylation and reduced expression in low-risk myelodysplastic syndromes.
abstract: Gene expression profiling signatures may be used to classify the subtypes of Myelodysplastic syndrome (MDS) patients. However, there are few reports on the global methylation status in MDS. The integration of genome-wide epigenetic regulatory marks with gene expression levels would provide additional information regarding the biological differences between MDS and healthy controls. Gene expression and methylation status were measured using high-density microarrays. A total of 552 differentially methylated CpG loci were identified as being present in low-risk MDS; hypermethylated genes were more frequent than hypomethylated genes. In addition, mRNA expression profiling identified 1005 genes that significantly differed between low-risk MDS and the control group. Integrative analysis of the epigenetic and expression profiles revealed that 66.7% of the hypermethylated genes were underexpressed in low-risk MDS cases. Gene network analysis revealed molecular mechanisms associated with the low-risk MDS group, including altered apoptosis pathways. The two key apoptotic genes BCL2 and ETS1 were identified as silenced genes. In addition, the immune response and micro RNA biogenesis were affected by the hypermethylation and underexpression of IL27RA and DICER1. Our integrative analysis revealed that aberrant epigenetic regulation is a hallmark of low-risk MDS patients and could have a central role in these diseases.
authors.affiliation: Centro de Investigación del Cáncer, Universidad de Salamanca-CSIC, Salamanca, Spain.
authors.forename: M
authors.initials: M
authors.lastname: del Rey
authors.forename: K
authors.initials: K
authors.lastname: O'Hagan
authors.forename: M
authors.initials: M
authors.lastname: Dellett
authors.forename: S
authors.initials: S
authors.lastname: Aibar
authors.forename: H A A
authors.initials: HA
authors.lastname: Colyer
authors.forename: M E
authors.initials: ME
authors.lastname: Alonso
authors.forename: M
authors.initials: M
authors.lastname: Díez-Campelo
authors.forename: R N
authors.initials: RN
authors.lastname: Armstrong
authors.forename: D J
authors.initials: DJ
authors.lastname: Sharpe
authors.forename: N C
authors.initials: NC
authors.lastname: Gutiérrez
authors.forename: J L
authors.initials: JL
authors.lastname: García
authors.forename: J
authors.initials: J
authors.lastname: De Las Rivas
authors.forename: K I
authors.initials: KI
authors.lastname: Mills
authors.forename: J M
authors.initials: JM
authors.lastname: Hernández-Rivas
mesh_terms: D014408:Biomarkers, Tumor / Q000235:genetics*; D016022:Case-Control Studies; D018899:CpG Islands / Q000235:genetics*; D053487:DEAD-box RNA Helicases / Q000235:genetics; D019175:DNA Methylation; D004273:DNA, Neoplasm / Q000235:genetics; D044127:Epigenesis, Genetic; D020869:Gene Expression Profiling; D015973:Gene Expression Regulation, Leukemic; D015894:Genome, Human; D006801:Humans; D009190:Myelodysplastic Syndromes / Q000235:genetics*; D020411:Oligonucleotide Array Sequence Analysis; D016133:Polymerase Chain Reaction; D011379:Prognosis; D050784:Proto-Oncogene Protein c-ets-1 / Q000235:genetics; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics; D018123:Receptors, Interleukin / Q000235:genetics; D043244:Ribonuclease III / Q000235:genetics; D012307:Risk Factors; D014407:Tumor Cells, Cultured
chemical_list: D014408:Biomarkers, Tumor; D004273:DNA, Neoplasm; C494041:ETS1 protein, human; C112441:IL27RA protein, human; D050784:Proto-Oncogene Protein c-ets-1; D019253:Proto-Oncogene Proteins c-bcl-2; D018123:Receptors, Interleukin; C408087:DICER1 protein, human; D043244:Ribonuclease III; D053487:DEAD-box RNA Helicases