title: Novel imprinted DLK1/GTL2 domain on human chromosome 14 contains motifs that mimic those implicated in IGF2/H19 regulation.
abstract: The evolution of genomic imprinting in mammals occurred more than 100 million years ago, and resulted in the formation of genes that are functionally haploid because of parent-of-origin-dependent expression. Despite ample evidence from studies in a number of species suggesting the presence of imprinted genes on human chromosome 14, their identity has remained elusive. Here we report the identification of two reciprocally imprinted genes, GTL2 and DLK1, which together define a novel imprinting cluster on human chromosome 14q32. The maternally expressed GTL2 (gene trap locus 2) gene encodes for a nontranslated RNA. DLK1 (delta, Drosophila, homolog-like 1) is a paternally expressed gene that encodes for a transmembrane protein containing six epidermal growth factor (EGF) repeat motifs closely related to those present in the delta/notch/serrate family of signaling molecules. The paternal expression, chromosomal localization, and biological function of DLK1 also make it a likely candidate gene for the callipyge phenotype in sheep. Many of the predicted structural and regulatory features of the DLK1/GTL2 domain are highly analogous to those implicated in IGF2/H19 imprint regulation, including two hemimethylated consensus binding sites for the vertebrate enhancer blocking protein, CTCF. These results provide evidence that a common mechanism and domain organization may be used for juxtapositioned, reciprocally imprinted genes.
authors.affiliation: Department of Radiation Oncology and Pathology, Duke University Medical Center, Durham, NC 27710, USA.
authors.forename: A A
authors.initials: AA
authors.lastname: Wylie
authors.forename: S K
authors.initials: SK
authors.lastname: Murphy
authors.forename: T C
authors.initials: TC
authors.lastname: Orton
authors.forename: R L
authors.initials: RL
authors.lastname: Jirtle
mesh_terms: D020816:Amino Acid Motifs / Q000235:genetics; D000818:Animals; D002880:Chromosomes, Human, Pair 11 / Q000235:genetics; D002883:Chromosomes, Human, Pair 14 / Q000235:genetics*; D019175:DNA Methylation; D005801:Genes, Homeobox; D018392:Genomic Imprinting / Q000235:genetics*; D006801:Humans; D007335:Insulin-Like Growth Factor II / Q000235:genetics* / Q000502:physiology; D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins / Q000235:genetics*; D051379:Mice; D016366:Open Reading Frames / Q000235:genetics; D017434:Protein Structure, Tertiary / Q000235:genetics; D062085:RNA, Long Noncoding; D022661:RNA, Untranslated / Q000235:genetics* / Q000502:physiology
chemical_list: C094335:H19 long non-coding RNA; D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins; D062085:RNA, Long Noncoding; D022661:RNA, Untranslated; C064045:delta protein; D007335:Insulin-Like Growth Factor II