Gene expression analysis of human induced pluripotent stem cell-derived neurons carrying copy number variants of chromosome 15q11-q13.1

Noelle D. Germain, Pin Fang Chen, Alex M. Plocik, Heather Glatt-Deeley, Judith Brown, James J. Fink, Kaitlyn A. Bolduc, Tiwanna M. Robinson, Eric S. Levine, Lawrence Reiter, Brenton R. Graveley, Marc Lalande, Stormy J. Chamberlain

Research output: Contribution to journalArticle

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Abstract

Background: Duplications of the chromosome 15q11-q13.1 region are ssociated 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.

Original languageEnglish (US)
Article number44
JournalMolecular Autism
Volume5
Issue number1
DOIs
StatePublished - Aug 20 2014

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Induced Pluripotent Stem Cells
Chromosomes
Gene Expression
Neurons
Angelman Syndrome
Cell Line
Ubiquitin-Protein Ligases
Chromosome Duplication
Genome
Genes
Messenger RNA
Inborn Genetic Diseases
Gene Dosage
Autistic Disorder
Chromosome Aberrations
Reverse Transcription
Chromatin
Stem Cells
Phenotype
Polymerase Chain Reaction

All Science Journal Classification (ASJC) codes

  • Molecular Biology
  • Developmental Neuroscience
  • Developmental Biology
  • Psychiatry and Mental health

Cite this

Germain, N. D., Chen, P. F., Plocik, A. M., Glatt-Deeley, H., Brown, J., Fink, J. J., ... Chamberlain, S. J. (2014). Gene expression analysis of human induced pluripotent stem cell-derived neurons carrying copy number variants of chromosome 15q11-q13.1. Molecular Autism, 5(1), [44]. https://doi.org/10.1186/2040-2392-5-44

Gene expression analysis of human induced pluripotent stem cell-derived neurons carrying copy number variants of chromosome 15q11-q13.1. / Germain, Noelle D.; Chen, Pin Fang; Plocik, Alex M.; Glatt-Deeley, Heather; Brown, Judith; Fink, James J.; Bolduc, Kaitlyn A.; Robinson, Tiwanna M.; Levine, Eric S.; Reiter, Lawrence; Graveley, Brenton R.; Lalande, Marc; Chamberlain, Stormy J.

In: Molecular Autism, Vol. 5, No. 1, 44, 20.08.2014.

Research output: Contribution to journalArticle

Germain, ND, Chen, PF, Plocik, AM, Glatt-Deeley, H, Brown, J, Fink, JJ, Bolduc, KA, Robinson, TM, Levine, ES, Reiter, L, Graveley, BR, Lalande, M & Chamberlain, SJ 2014, 'Gene expression analysis of human induced pluripotent stem cell-derived neurons carrying copy number variants of chromosome 15q11-q13.1', Molecular Autism, vol. 5, no. 1, 44. https://doi.org/10.1186/2040-2392-5-44
Germain, Noelle D. ; Chen, Pin Fang ; Plocik, Alex M. ; Glatt-Deeley, Heather ; Brown, Judith ; Fink, James J. ; Bolduc, Kaitlyn A. ; Robinson, Tiwanna M. ; Levine, Eric S. ; Reiter, Lawrence ; Graveley, Brenton R. ; Lalande, Marc ; Chamberlain, Stormy J. / Gene expression analysis of human induced pluripotent stem cell-derived neurons carrying copy number variants of chromosome 15q11-q13.1. In: Molecular Autism. 2014 ; Vol. 5, No. 1.
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AU - Germain, Noelle D.

AU - Chen, Pin Fang

AU - Plocik, Alex M.

AU - Glatt-Deeley, Heather

AU - Brown, Judith

AU - Fink, James J.

AU - Bolduc, Kaitlyn A.

AU - Robinson, Tiwanna M.

AU - Levine, Eric S.

AU - Reiter, Lawrence

AU - Graveley, Brenton R.

AU - Lalande, Marc

AU - Chamberlain, Stormy J.

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N2 - Background: Duplications of the chromosome 15q11-q13.1 region are ssociated 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.

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