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

• Published in: Molecular autism Vol. 9; no. 1; pp. 6 - 16
• Main Authors: 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 T.
• Format: Journal Article
• Language: English
• Published: England BioMed Central Ltd 27.01.2018; BioMed Central; BMC
• Subjects: Angelman syndrome; Angelman Syndrome - genetics; Angelman Syndrome - metabolism; Autism; Basic Helix-Loop-Helix Transcription Factors - genetics; Basic Helix-Loop-Helix Transcription Factors - metabolism; Cells, Cultured; Chromosome Deletion; Chromosomes, Human, Pair 15 - genetics; Chromosomes, Human, Pair 15 - metabolism; Dental Pulp - cytology; Development and progression; DNA binding proteins; Forkhead Box Protein O1 - genetics; Forkhead Box Protein O1 - metabolism; Gene expression; Genetic aspects; Genomic disorders; Guanine Nucleotide Exchange Factors - genetics; Guanine Nucleotide Exchange Factors - metabolism; Humans; mRNAseq; Neural Stem Cells - metabolism; Neurogenetic syndrome; Nuclear Receptor Subfamily 1, Group F, Member 1 - genetics; Nuclear Receptor Subfamily 1, Group F, Member 1 - metabolism; Physiological aspects; Stem cells; Transcriptome; Trisomy - genetics; Ubiquitin-Protein Ligases - genetics; Ubiquitin-Protein Ligases - metabolism; United States; United Kingdom; Genomic disorders; mRNAseq; Autism; Neurogenetic syndrome; Stem cells
• ISSN: 2040-2392; 2040-2392
• DOI: 10.1186/s13229-018-0191-y

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. 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. 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 and 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 and , 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. Finding a significant increase in both and in Dup15q neurons and significant decrease in these two genes in AS deletion neurons may explain differences between AS deletion class and specific classes of AS mutation where is expressed at normal levels. Also, we identified an enrichment for FOXO1-regulated transcripts in Dup15q neurons including ASD-associated genes and indicating a possible connection between this syndromic form of ASD and idiopathic cases.