Significant transcriptional changes in 15q duplication but not Angelman syndrome deletion stem cell-derived neurons

Nora Urraca, Kevin Hope, A. Kaitlyn Victor, T. Grant Belgard, Rawaha Memon, Sarita Goorha, Colleen Valdez, Quynh T. Tran, Silvia Sanchez, Juanma Ramirez, Martin Donaldson, Dave Bridges, Lawrence Reiter

Research output: Contribution to journalArticle

2 Citations (Scopus)

Abstract

Background: The inability to analyze gene expression in living neurons from Angelman (AS) and Duplication 15q (Dup15q) syndrome subjects has limited our understanding of these disorders at the molecular level. Method: Here, we use dental pulp stem cells (DPSC) from AS deletion, 15q Duplication, and neurotypical control subjects for whole transcriptome analysis. We identified 20 genes unique to AS neurons, 120 genes unique to 15q duplication, and 3 shared transcripts that were differentially expressed in DPSC neurons vs controls. Results: Copy number correlated with gene expression for most genes across the 15q11.2-q13.1 critical region. Two thirds of the genes differentially expressed in 15q duplication neurons were downregulated compared to controls including several transcription factors, while in AS differential expression was restricted primarily to the 15q region. Here, we show significant downregulation of the transcription factors FOXO1 and HAND2 in neurons from 15q duplication, but not AS deletion subjects suggesting that disruptions in transcriptional regulation may be a driving factor in the autism phenotype in Dup15q syndrome. Downstream analysis revealed downregulation of the ASD associated genes EHPB2 and RORA, both genes with FOXO1 binding sites. Genes upregulated in either Dup15q cortex or idiopathic ASD cortex both overlapped significantly with the most upregulated genes in Dup15q DPSC-derived neurons. Conclusions: Finding a significant increase in both HERC2 and UBE3A in Dup15q neurons and significant decrease in these two genes in AS deletion neurons may explain differences between AS deletion class and UBE3A specific classes of AS mutation where HERC2 is expressed at normal levels. Also, we identified an enrichment for FOXO1-regulated transcripts in Dup15q neurons including ASD-associated genes EHPB2 and RORA indicating a possible connection between this syndromic form of ASD and idiopathic cases.

Original languageEnglish (US)
Article number6
JournalMolecular Autism
Volume9
Issue number1
DOIs
StatePublished - Jan 27 2018

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Angelman Syndrome
Stem Cells
Neurons
Genes
Dental Pulp
Down-Regulation
Transcription Factors
Trisomy Chromosome 15q
Gene Expression
Gene Duplication
Gene Expression Profiling
Autistic Disorder
Binding Sites

All Science Journal Classification (ASJC) codes

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

Cite this

Significant transcriptional changes in 15q duplication but not Angelman syndrome deletion stem cell-derived neurons. / Urraca, Nora; Hope, Kevin; Victor, A. Kaitlyn; Belgard, T. Grant; Memon, Rawaha; Goorha, Sarita; Valdez, Colleen; Tran, Quynh T.; Sanchez, Silvia; Ramirez, Juanma; Donaldson, Martin; Bridges, Dave; Reiter, Lawrence.

In: Molecular Autism, Vol. 9, No. 1, 6, 27.01.2018.

Research output: Contribution to journalArticle

Urraca, N, Hope, K, Victor, AK, Belgard, TG, Memon, R, Goorha, S, Valdez, C, Tran, QT, Sanchez, S, Ramirez, J, Donaldson, M, Bridges, D & Reiter, L 2018, 'Significant transcriptional changes in 15q duplication but not Angelman syndrome deletion stem cell-derived neurons', Molecular Autism, vol. 9, no. 1, 6. https://doi.org/10.1186/s13229-018-0191-y
Urraca, Nora ; Hope, Kevin ; Victor, A. Kaitlyn ; Belgard, T. Grant ; Memon, Rawaha ; Goorha, Sarita ; Valdez, Colleen ; Tran, Quynh T. ; Sanchez, Silvia ; Ramirez, Juanma ; Donaldson, Martin ; Bridges, Dave ; Reiter, Lawrence. / Significant transcriptional changes in 15q duplication but not Angelman syndrome deletion stem cell-derived neurons. In: Molecular Autism. 2018 ; Vol. 9, No. 1.
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AU - Memon, Rawaha

AU - Goorha, Sarita

AU - Valdez, Colleen

AU - Tran, Quynh T.

AU - Sanchez, Silvia

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AU - Donaldson, Martin

AU - Bridges, Dave

AU - Reiter, Lawrence

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