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

Abstract

BackgroundThe 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.MethodHere, 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.ResultsCopy 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.ConclusionsFinding 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.Electronic supplementary materialThe online version of this article (10.1186/s13229-018-0191-y) contains supplementary material, which is available to authorized users.

Alterations in the autonomic nerve activities of prenatal autism model mice treated with valproic acid at different developmental stages

“…Therefore, the assessment of the sympathetic nerve activity may be useful for the early diagnosis of ASD. It has been reported that the expression of the HAND2 gene, which encodes a transcription factor and is required for sympathetic neuron survival 35 , was decreased in neurons derived from human Chr. 15q11.2-q13.1 duplicated ASD stem cells 35 .…”

“…It has been reported that the expression of the HAND2 gene, which encodes a transcription factor and is required for sympathetic neuron survival 35 , was decreased in neurons derived from human Chr. 15q11.2-q13.1 duplicated ASD stem cells 35 . Hence, our results of lower activities of the sympathetic nervous system in the fetal stage of the ASD model mice could explain the impaired sympathetic survival and/or development detected in ASD.…”

“…5D). Finally, regarding the LF(ln)/HF(ln) ratio, there were no main effects of sex (F[1,35] = 0.640, P = 0.429), treatment (F[1, 35] = 0.080, P = 0.778), and interaction of sex with treatment (F[1, 35] = 0.577, P = 0.453)(Fig. 5E).…”

Genetic interaction screen for severe neurodevelopmental disorders reveals a functional link between Ube3a and Mef2 in Drosophila melanogaster

“…However, a transcriptional regulation mechanism appears unlikely as in flies expression levels of Mef2 were unaltered upon Ube3a knockdown and vice versa, and as in a human cell line UBE3A knockdown did not change MEF2C expression levels. Additionally, stem cell-derived neurons modelling Angelman syndrome, did not show significant transcriptional changes of other genes (compared to 15q duplication neurons) 52 . As the most likely hypothesis, we suggest that UBE3A might regulate MEF2C activity and levels by ubiquitination, leading to subsequent degradation in the proteasome.…”

Human Models Are Needed for Studying Human Neurodevelopmental Disorders

“…PSC models of neurodevelopmental disorders caused by mutations in single genes have been established and include those for Rett syndrome (MECP2 [MIM: 300005]), [304][305][306][307][308] tuberous sclerosis (TSC1 [MIM: 605284]), [309][310][311] and FXS. [312][313][314][315][316] More complex genetic disorders have benefitted from the ability to retain the chromosomal defect in hiPSCs for disorders that result in deletions or duplications of chromosomal regions, such as 15q11.2 microdeletion syndrome (MIM: 615656), 317 Prader-Willi syndrome (MIM: 608636), 318,319 and DS. [320][321][322][323][324] Some phenotypes in neural cells derived from these cells link to disease symptomology, whereas other phenotypes do not, and there is variability in the phenotypes in different reports.…”