title: Angelman syndrome-derived neurons display late onset of paternal UBE3A silencing.
abstract: Genomic imprinting is an epigenetic phenomenon resulting in parent-of-origin-specific gene expression that is regulated by a differentially methylated region. Gene mutations or failures in the imprinting process lead to the development of imprinting disorders, such as Angelman syndrome. The symptoms of Angelman syndrome are caused by the absence of functional UBE3A protein in neurons of the brain. To create a human neuronal model for Angelman syndrome, we reprogrammed dermal fibroblasts of a patient carrying a defined three-base pair deletion in UBE3A into induced pluripotent stem cells (iPSCs). In these iPSCs, both parental alleles are present, distinguishable by the mutation, and express UBE3A. Detailed characterization of these iPSCs demonstrated their pluripotency and exceptional stability of the differentially methylated region regulating imprinted UBE3A expression. We observed strong induction of SNHG14 and silencing of paternal UBE3A expression only late during neuronal differentiation, in vitro. This new Angelman syndrome iPSC line allows to study imprinted gene regulation on both parental alleles and to dissect molecular pathways affected by the absence of UBE3A protein.
authors.affiliation: Institute of Human Genetics, University Hospital Essen, University of Duisburg-Essen, Hufelandstr. 55, 45147 Essen, Germany.
authors.forename: Jana
authors.initials: J
authors.lastname: Stanurova
authors.affiliation: Institute for Transfusion Medicine, University Hospital Essen, University of Duisburg-Essen, Hufelandstr. 55, 45147 Essen, Germany.
authors.forename: Anika
authors.initials: A
authors.lastname: Neureiter
authors.affiliation: Institute of Human Genetics, University Hospital Essen, University of Duisburg-Essen, Hufelandstr. 55, 45147 Essen, Germany.
authors.forename: Michaela
authors.initials: M
authors.lastname: Hiber
authors.affiliation: Institute for Transfusion Medicine, University Hospital Essen, University of Duisburg-Essen, Hufelandstr. 55, 45147 Essen, Germany.
authors.forename: Hannah
authors.initials: H
authors.lastname: de Oliveira Kessler
authors.affiliation: Institute for Transfusion Medicine, University Hospital Essen, University of Duisburg-Essen, Hufelandstr. 55, 45147 Essen, Germany.
authors.forename: Kristin
authors.initials: K
authors.lastname: Stolp
authors.affiliation: Helmholtz Institute for Biomedical Engineering, Stem Cell Biology and Cellular Engineering, RWTH Aachen University, Pauwelsstr. 20, 52074 Aachen, Germany.
authors.forename: Roman
authors.initials: R
authors.lastname: Goetzke
authors.affiliation: Institute for Cell Biology, University Hospital Essen, University of Duisburg-Essen, Hufelandstr. 55, 45147 Essen, Germany.
authors.forename: Diana
authors.initials: D
authors.lastname: Klein
authors.affiliation: Institute of Pathology, University Hospital Essen, University of Duisburg-Essen, Hufelandstr. 55, 45147 Essen, Germany.
authors.forename: Agnes
authors.initials: A
authors.lastname: Bankfalvi
authors.affiliation: Institute for Transfusion Medicine, University Hospital Essen, University of Duisburg-Essen, Hufelandstr. 55, 45147 Essen, Germany.
authors.forename: Hannes
authors.initials: H
authors.lastname: Klump
authors.affiliation: Institute of Human Genetics, University Hospital Essen, University of Duisburg-Essen, Hufelandstr. 55, 45147 Essen, Germany.
authors.forename: Laura
authors.initials: L
authors.lastname: Steenpass
mesh_terms: D017204:Angelman Syndrome / Q000235:genetics* / Q000378:metabolism; D020134:Catalytic Domain; D002454:Cell Differentiation; D000067470:Cellular Reprogramming Techniques / Q000379:methods; D019175:DNA Methylation; D020405:Dermis / Q000166:cytology / Q000378:metabolism; D044127:Epigenesis, Genetic; D005260:Female; D005347:Fibroblasts / Q000166:cytology / Q000378:metabolism; D018392:Genomic Imprinting; D006801:Humans; D057026:Induced Pluripotent Stem Cells / Q000166:cytology* / Q000378:metabolism; D008954:Models, Biological; D009474:Neurons / Q000166:cytology* / Q000378:metabolism; D011485:Protein Binding; D017384:Sequence Deletion; D044767:Ubiquitin-Protein Ligases / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism
chemical_list: C471639:UBE3A protein, human; D044767:Ubiquitin-Protein Ligases