title: Differentially methylated regions in maternal and paternal uniparental disomy for chromosome 7.
abstract: DNA methylation is a hallmark of genomic imprinting and differentially methylated regions (DMRs) are found near and in imprinted genes. Imprinted genes are expressed only from the maternal or paternal allele and their normal balance can be disrupted by uniparental disomy (UPD), the inheritance of both chromosomes of a chromosome pair exclusively from only either the mother or the father. Maternal UPD for chromosome 7 (matUPD7) results in Silver-Russell syndrome (SRS) with typical features and growth retardation, but no gene has been conclusively implicated in SRS. In order to identify novel DMRs and putative imprinted genes on chromosome 7, we analyzed eight matUPD7 patients, a segmental matUPD7q31-qter, a rare patUPD7 case and ten controls on the Infinium HumanMethylation450K BeadChip with 30 017 CpG methylation probes for chromosome 7. Genome-scale analysis showed highly significant clustering of DMRs only on chromosome 7, including the known imprinted loci GRB10, SGCE/PEG10, and PEG/MEST. We found ten novel DMRs on chromosome 7, two DMRs for the predicted imprinted genes HOXA4 and GLI3 and one for the disputed imprinted gene PON1. Quantitative RT-PCR on blood RNA samples comparing matUPD7, patUPD7, and controls showed differential expression for three genes with novel DMRs, HOXA4, GLI3, and SVOPL. Allele specific expression analysis confirmed maternal only expression of SVOPL and imprinting of HOXA4 was supported by monoallelic expression. These results present the first comprehensive map of parent-of-origin specific DMRs on human chromosome 7, suggesting many new imprinted sites.
authors.affiliation: Department of Medical Genetics; Haartman Institute; Molecular Neurology Program; Research Program's Unit; Folkhälsan Institute of Genetics; University of Helsinki; Helsinki, Finland; Department of Dermatology and Allergology; Skin and Allergy Hospital; Helsinki University Central Hospital; Helsinki University Hospital; Helsinki, Finland.
authors.forename: Katariina
authors.initials: K
authors.lastname: Hannula-Jouppi
authors.affiliation: Department of Medical Genetics; Haartman Institute; Molecular Neurology Program; Research Program's Unit; Folkhälsan Institute of Genetics; University of Helsinki; Helsinki, Finland.
authors.forename: Mari
authors.initials: M
authors.lastname: Muurinen
authors.affiliation: Children's Hospital; University of Helsinki and Helsinki University Central Hospital; Helsinki University Hospital; Helsinki, Finland.
authors.forename: Marita
authors.initials: M
authors.lastname: Lipsanen-Nyman
authors.affiliation: Department of Biosciences and Nutrition; Center for Biosciences; Karolinska Institutet; Stockholm, Sweden.
authors.forename: Lovisa E
authors.initials: LE
authors.lastname: Reinius
authors.affiliation: Department of Medical Genetics; Haartman Institute; Molecular Neurology Program; Research Program's Unit; Folkhälsan Institute of Genetics; University of Helsinki; Helsinki, Finland.
authors.forename: Sini
authors.initials: S
authors.lastname: Ezer
authors.affiliation: Department of Medical Genetics; Haartman Institute; Molecular Neurology Program; Research Program's Unit; Folkhälsan Institute of Genetics; University of Helsinki; Helsinki, Finland; Department of Biosciences and Nutrition; Center for Biosciences; Karolinska Institutet; Stockholm, Sweden; Unit of Systems Toxicology; Finnish Institute of Occupational Health (FIOH); Helsinki, Finland.
authors.forename: Dario
authors.initials: D
authors.lastname: Greco
authors.affiliation: Department of Medical Genetics; Haartman Institute; Molecular Neurology Program; Research Program's Unit; Folkhälsan Institute of Genetics; University of Helsinki; Helsinki, Finland; Department of Biosciences and Nutrition; Center for Biosciences; Karolinska Institutet; Stockholm, Sweden; Science for Life Laboratory; Karolinska Institutet; Solna, Sweden.
authors.forename: Juha
authors.initials: J
authors.lastname: Kere
mesh_terms: D000483:Alleles; D002897:Chromosomes, Human, Pair 7 / Q000235:genetics*; D019175:DNA Methylation; D005260:Female; D018392:Genomic Imprinting; D018398:Homeodomain Proteins / Q000235:genetics; D006801:Humans; D051741:Kruppel-Like Transcription Factors / Q000235:genetics; D008297:Male; D009419:Nerve Tissue Proteins / Q000235:genetics; D056730:Silver-Russell Syndrome / Q000235:genetics; D014157:Transcription Factors; D024182:Uniparental Disomy; D000074290:Zinc Finger Protein Gli3
chemical_list: C065683:GLI3 protein, human; D018398:Homeodomain Proteins; D051741:Kruppel-Like Transcription Factors; D009419:Nerve Tissue Proteins; D014157:Transcription Factors; D000074290:Zinc Finger Protein Gli3; C073547:HOXA4 protein, human
keywords: Silver-Russell syndrome; chromosome 7; differentially methylated regions; genome-scale analysis; imprinting; methylation; uniparental disomy