title: The human retinoblastoma gene is imprinted.
abstract: Genomic imprinting is an epigenetic process leading to parent-of-origin-specific DNA methylation and gene expression. To date, approximately 60 imprinted human genes are known. Based on genome-wide methylation analysis of a patient with multiple imprinting defects, we have identified a differentially methylated CpG island in intron 2 of the retinoblastoma (RB1) gene on chromosome 13. The CpG island is part of a 5'-truncated, processed pseudogene derived from the KIAA0649 gene on chromosome 9 and corresponds to two small CpG islands in the open reading frame of the ancestral gene. It is methylated on the maternal chromosome 13 and acts as a weak promoter for an alternative RB1 transcript on the paternal chromosome 13. In four other KIAA0649 pseudogene copies, which are located on chromosome 22, the two CpG islands have deteriorated and the CpG dinucleotides are fully methylated. By analysing allelic RB1 transcript levels in blood cells, as well as in hypermethylated and 5-aza-2'-deoxycytidine-treated lymphoblastoid cells, we have found that differential methylation of the CpG island skews RB1 gene expression in favor of the maternal allele. Thus, RB1 is imprinted in the same direction as CDKN1C, which operates upstream of RB1. The imprinting of two components of the same pathway indicates that there has been strong evolutionary selection for maternal inhibition of cell proliferation.
authors.affiliation: Institut für Humangenetik, Universitätsklinikum Essen, Essen, Germany.
authors.forename: Deniz
authors.initials: D
authors.lastname: Kanber
authors.forename: Tea
authors.initials: T
authors.lastname: Berulava
authors.forename: Ole
authors.initials: O
authors.lastname: Ammerpohl
authors.forename: Diana
authors.initials: D
authors.lastname: Mitter
authors.forename: Julia
authors.initials: J
authors.lastname: Richter
authors.forename: Reiner
authors.initials: R
authors.lastname: Siebert
authors.forename: Bernhard
authors.initials: B
authors.lastname: Horsthemke
authors.forename: Dietmar
authors.initials: D
authors.lastname: Lohmann
authors.forename: Karin
authors.initials: K
authors.lastname: Buiting
mesh_terms: D022981:Allelic Imbalance / Q000187:drug effects / Q000235:genetics; D000818:Animals; D001374:Azacitidine / Q000494:pharmacology; D018899:CpG Islands / Q000235:genetics; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation / Q000187:drug effects; D056426:Genetic Loci / Q000235:genetics; D018392:Genomic Imprinting / Q000187:drug effects / Q000235:genetics*; D006801:Humans; D008214:Lymphocytes / Q000187:drug effects / Q000378:metabolism; D008253:Macaca mulatta / Q000235:genetics; D002679:Pan troglodytes / Q000235:genetics; D011544:Pseudogenes / Q000235:genetics; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D016160:Retinoblastoma Protein / Q000235:genetics*
chemical_list: D012333:RNA, Messenger; D016160:Retinoblastoma Protein; D001374:Azacitidine