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Epigenetics. 2014 Mar;9(3):351-65. doi: 10.4161/epi.27160. Epub 2013 Nov 18.

Differentially methylated regions in maternal and paternal uniparental disomy for chromosome 7.

Author information

1
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.
2
Department of Medical Genetics; Haartman Institute; Molecular Neurology Program; Research Program's Unit; Folkhälsan Institute of Genetics; University of Helsinki; Helsinki, Finland.
3
Children's Hospital; University of Helsinki and Helsinki University Central Hospital; Helsinki University Hospital; Helsinki, Finland.
4
Department of Biosciences and Nutrition; Center for Biosciences; Karolinska Institutet; Stockholm, Sweden.
5
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.
6
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.

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.

KEYWORDS:

Silver-Russell syndrome; chromosome 7; differentially methylated regions; genome-scale analysis; imprinting; methylation; uniparental disomy

PMID:
24247273
PMCID:
PMC4053454
DOI:
10.4161/epi.27160
[Indexed for MEDLINE]
Free PMC Article

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