title: The noncoding RNA IPW regulates the imprinted DLK1-DIO3 locus in an induced pluripotent stem cell model of Prader-Willi syndrome.
abstract: Parental imprinting is a form of epigenetic regulation that results in parent-of-origin differential gene expression. To study Prader-Willi syndrome (PWS), a developmental imprinting disorder, we generated case-derived induced pluripotent stem cells (iPSCs) harboring distinct aberrations in the affected region on chromosome 15. In studying PWS-iPSCs and human parthenogenetic iPSCs, we unexpectedly found substantial upregulation of virtually all maternally expressed genes (MEGs) in the imprinted DLK1-DIO3 locus on chromosome 14. Subsequently, we determined that IPW, a long noncoding RNA in the critical region of the PWS locus, is a regulator of the DLK1-DIO3 region, as its overexpression in PWS and parthenogenetic iPSCs resulted in downregulation of MEGs in this locus. We further show that gene expression changes in the DLK1-DIO3 region coincide with chromatin modifications rather than DNA methylation levels. Our results suggest that a subset of PWS phenotypes may arise from dysregulation of an imprinted locus distinct from the PWS region.
authors.affiliation: Stem Cell Unit, Department of Genetics, Institute of Life Sciences, The Hebrew University, Jerusalem, Israel.
authors.forename: Yonatan
authors.initials: Y
authors.lastname: Stelzer
authors.affiliation: Stem Cell Unit, Department of Genetics, Institute of Life Sciences, The Hebrew University, Jerusalem, Israel.
authors.forename: Ido
authors.initials: I
authors.lastname: Sagi
authors.affiliation: Stem Cell Unit, Department of Genetics, Institute of Life Sciences, The Hebrew University, Jerusalem, Israel.
authors.forename: Ofra
authors.initials: O
authors.lastname: Yanuka
authors.affiliation: Stem Cell Research Laboratory, Shaare Zedek Medical Center, The Hebrew University, Jerusalem, Israel.
authors.forename: Rachel
authors.initials: R
authors.lastname: Eiges
authors.affiliation: Stem Cell Unit, Department of Genetics, Institute of Life Sciences, The Hebrew University, Jerusalem, Israel.
authors.forename: Nissim
authors.initials: N
authors.lastname: Benvenisty
mesh_terms: D000293:Adolescent; D001921:Brain / Q000378:metabolism; D002135:Calcium-Binding Proteins; D002843:Chromatin / Q000378:metabolism; D002869:Chromosome Aberrations; D019175:DNA Methylation; D015536:Down-Regulation; D005347:Fibroblasts / Q000378:metabolism; D020869:Gene Expression Profiling; D055106:Genome-Wide Association Study; D018392:Genomic Imprinting; D006801:Humans; D057026:Induced Pluripotent Stem Cells / Q000166:cytology*; D007223:Infant; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics*; D007453:Iodide Peroxidase / Q000235:genetics*; D008297:Male; D008565:Membrane Proteins / Q000235:genetics*; D020411:Oligonucleotide Array Sequence Analysis; D010641:Phenotype; D011218:Prader-Willi Syndrome / Q000235:genetics*; D022661:RNA, Untranslated / Q000235:genetics*; D014158:Transcription, Genetic; D059467:Transcriptome
chemical_list: D002135:Calcium-Binding Proteins; D002843:Chromatin; C512941:DLK1 protein, human; D036341:Intercellular Signaling Peptides and Proteins; D008565:Membrane Proteins; D022661:RNA, Untranslated; C117274:iodothyronine deiodinase type III; D007453:Iodide Peroxidase