title: Gene expression analysis of human induced pluripotent stem cell-derived neurons carrying copy number variants of chromosome 15q11-q13.1.
abstract: BACKGROUND
  Duplications of the chromosome 15q11-q13.1 region are associated with an estimated 1 to 3% of all autism cases, making this copy number variation (CNV) one of the most frequent chromosome abnormalities associated with autism spectrum disorder (ASD). Several genes located within the 15q11-q13.1 duplication region including ubiquitin protein ligase E3A (UBE3A), the gene disrupted in Angelman syndrome (AS), are involved in neural function and may play important roles in the neurobehavioral phenotypes associated with chromosome 15q11-q13.1 duplication (Dup15q) syndrome.
  
  
  METHODS
  We have generated induced pluripotent stem cell (iPSC) lines from five different individuals containing CNVs of 15q11-q13.1. The iPSC lines were differentiated into mature, functional neurons. Gene expression across the 15q11-q13.1 locus was compared among the five iPSC lines and corresponding iPSC-derived neurons using quantitative reverse transcription PCR (qRT-PCR). Genome-wide gene expression was compared between neurons derived from three iPSC lines using mRNA-Seq.
  
  
  RESULTS
  Analysis of 15q11-q13.1 gene expression in neurons derived from Dup15q iPSCs reveals that gene copy number does not consistently predict expression levels in cells with interstitial duplications of 15q11-q13.1. mRNA-Seq experiments show that there is substantial overlap in the genes differentially expressed between 15q11-q13.1 deletion and duplication neurons, Finally, we demonstrate that UBE3A transcripts can be pharmacologically rescued to normal levels in iPSC-derived neurons with a 15q11-q13.1 duplication.
  
  
  CONCLUSIONS
  Chromatin structure may influence gene expression across the 15q11-q13.1 region in neurons. Genome-wide analyses suggest that common neuronal pathways may be disrupted in both the Angelman and Dup15q syndromes. These data demonstrate that our disease-specific stem cell models provide a new tool to decipher the underlying cellular and genetic disease mechanisms of ASD and may also offer a pathway to novel therapeutic intervention in Dup15q syndrome.
authors.affiliation: Department of Genetics and Developmental Biology, University of Connecticut Health Center, 400 Farmington Avenue, Farmington, CT 06032, USA.
authors.forename: Noelle D
authors.initials: ND
authors.lastname: Germain
authors.affiliation: Department of Genetics and Developmental Biology, University of Connecticut Health Center, 400 Farmington Avenue, Farmington, CT 06032, USA.
authors.forename: Pin-Fang
authors.initials: PF
authors.lastname: Chen
authors.affiliation: Department of Genetics and Developmental Biology, University of Connecticut Health Center, 400 Farmington Avenue, Farmington, CT 06032, USA.
authors.forename: Alex M
authors.initials: AM
authors.lastname: Plocik
authors.affiliation: Department of Genetics and Developmental Biology, University of Connecticut Health Center, 400 Farmington Avenue, Farmington, CT 06032, USA.
authors.forename: Heather
authors.initials: H
authors.lastname: Glatt-Deeley
authors.affiliation: Chromosome Core, Department of Molecular and Cell Biology and Department of Allied Health Sciences, University of Connecticut, 354 Mansfield Road, Storrs, CT 06269, USA.
authors.forename: Judith
authors.initials: J
authors.lastname: Brown
authors.affiliation: Department of Neuroscience, University of Connecticut Health Center, 263 Farmington Avenue, Farmington, CT 06030, USA.
authors.forename: James J
authors.initials: JJ
authors.lastname: Fink
authors.affiliation: Department of Neuroscience, University of Connecticut Health Center, 263 Farmington Avenue, Farmington, CT 06030, USA.
authors.forename: Kaitlyn A
authors.initials: KA
authors.lastname: Bolduc
authors.affiliation: Department of Neuroscience, University of Connecticut Health Center, 263 Farmington Avenue, Farmington, CT 06030, USA.
authors.forename: Tiwanna M
authors.initials: TM
authors.lastname: Robinson
authors.affiliation: Department of Neuroscience, University of Connecticut Health Center, 263 Farmington Avenue, Farmington, CT 06030, USA.
authors.forename: Eric S
authors.initials: ES
authors.lastname: Levine
authors.affiliation: Department of Neurology, University of Tennessee Health Science Center, 855 Monroe Avenue, Suite 415, Memphis, TN 38163, USA.
authors.forename: Lawrence T
authors.initials: LT
authors.lastname: Reiter
authors.affiliation: Department of Genetics and Developmental Biology, University of Connecticut Health Center, 400 Farmington Avenue, Farmington, CT 06032, USA ; University of Connecticut Institute for Systems Genomics, Farmington, CT 06030, USA.
authors.forename: Brenton R
authors.initials: BR
authors.lastname: Graveley
authors.affiliation: Department of Genetics and Developmental Biology, University of Connecticut Health Center, 400 Farmington Avenue, Farmington, CT 06032, USA.
authors.forename: Marc
authors.initials: M
authors.lastname: Lalande
authors.affiliation: Department of Genetics and Developmental Biology, University of Connecticut Health Center, 400 Farmington Avenue, Farmington, CT 06032, USA.
authors.forename: Stormy J
authors.initials: SJ
authors.lastname: Chamberlain
keywords: 15q duplication; Angelman syndrome; UBE3A; autism; induced pluripotent stem cells