title: Methylation profiling in individuals with uniparental disomy identifies novel differentially methylated regions on chromosome 15.
abstract: The maternal and paternal genomes possess distinct epigenetic marks that distinguish them at imprinted loci. In order to identify imprinted loci, we used a novel method, taking advantage of the fact that uniparental disomy (UPD) provides a system that allows the two parental chromosomes to be studied independently. We profiled the paternal and maternal methylation on chromosome 15 using immunoprecipitation of methylated DNA and hybridization to tiling oligonucleotide arrays. Comparison of six individuals with maternal versus paternal UPD15 revealed 12 differentially methylated regions (DMRs). Putative DMRs were validated by bisulfite sequencing, confirming the presence of parent-of-origin-specific methylation marks. We detected DMRs associated with known imprinted genes within the Prader-Willi/Angelman syndrome region, such as SNRPN and MAGEL2, validating this as a method of detecting imprinted loci. Of the 12 DMRs identified, eight were novel, some of which are associated with genes not previously thought to be imprinted. These include a site within intron 2 of IGF1R at 15q26.3, a gene that plays a fundamental role in growth, and an intergenic site upstream of GABRG3 that lies within a previously defined candidate region conferring an increased maternal risk of psychosis. These data provide a map of parent-of-origin-specific epigenetic modifications on chromosome 15, identifying DNA elements that may play a functional role in the imprinting process. Application of this methodology to other chromosomes for which UPD has been reported will allow the systematic identification of imprinted sites throughout the genome.
authors.affiliation: Department of Genetic Medicine and Development, University of Geneva, Geneva 1211, Switzerland. andrew.sharp@mssm.edu
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Sharp
authors.forename: Eugenia
authors.initials: E
authors.lastname: Migliavacca
authors.forename: Yann
authors.initials: Y
authors.lastname: Dupre
authors.forename: Elisavet
authors.initials: E
authors.lastname: Stathaki
authors.forename: Mohammad Reza
authors.initials: MR
authors.lastname: Sailani
authors.forename: Alessandra
authors.initials: A
authors.lastname: Baumer
authors.forename: Albert
authors.initials: A
authors.lastname: Schinzel
authors.forename: Deborah J
authors.initials: DJ
authors.lastname: Mackay
authors.forename: David O
authors.initials: DO
authors.lastname: Robinson
authors.forename: Gilda
authors.initials: G
authors.lastname: Cobellis
authors.forename: Luigi
authors.initials: L
authors.lastname: Cobellis
authors.forename: Han G
authors.initials: HG
authors.lastname: Brunner
authors.forename: Bernhard
authors.initials: B
authors.lastname: Steiner
authors.forename: Stylianos E
authors.initials: SE
authors.lastname: Antonarakis
mesh_terms: D017204:Angelman Syndrome / Q000235:genetics; D002884:Chromosomes, Human, Pair 15 / Q000235:genetics*; D004247:DNA / Q000378:metabolism; D019175:DNA Methylation; D020869:Gene Expression Profiling; D006801:Humans; D011218:Prader-Willi Syndrome / Q000235:genetics; D011506:Proteins / Q000235:genetics; D024182:Uniparental Disomy / Q000235:genetics*; D055517:snRNP Core Proteins / Q000235:genetics; D047908:Intracellular Signaling Peptides and Proteins; D064267:Intrinsically Disordered Proteins
chemical_list: D004247:DNA; D011506:Proteins; D055517:snRNP Core Proteins; C510822:MAGEL2 protein, human; D047908:Intracellular Signaling Peptides and Proteins; D064267:Intrinsically Disordered Proteins