Heat Shock Alters the Expression of Schizophrenia and Autism Candidate Genes in an Induced Pluripotent Stem Cell Model of the Human Telencephalon

Lin, Mingyan; Zhao, Dejian; Hrabovsky, Anastasia; Pedrosa, Erika; Zheng, Deyou; Lachman, Herbert M.

doi:10.1371/journal.pone.0094968

Cited by 41 publications

(38 citation statements)

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“…with strong links to psychiatric and neurodevelopmental disorders and synaptic function and neuronal excitability ( Fig. 5b) [62][63][64][65][66][67][68][69][70][71][72]. Of note, two different isoforms from Circadian Locomotor Output Cycles Kaput (Clock), a gene involved in circadian rhythms and linked to depression and BD [73][74][75], were found to be differently altered (one more than threefold reduced and one more than fourfold increased) by circHomer1a knockdown (Fig.…”

Section: In Vivo Ofc Circhomer1a Knockdown Impairs Ofcmediated Behavimentioning

confidence: 99%

A psychiatric disease-related circular RNA controls synaptic gene expression and cognition

et al. 2020

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Although circular RNAs (circRNAs) are enriched in the mammalian brain, very little is known about their potential involvement in brain function and psychiatric disease. Here, we show that circHomer1a, a neuronal-enriched circRNA abundantly expressed in the frontal cortex, derived from Homer protein homolog 1 (HOMER1), is significantly reduced in both the prefrontal cortex (PFC) and induced pluripotent stem cell-derived neuronal cultures from patients with schizophrenia (SCZ) and bipolar disorder (BD). Moreover, alterations in circHomer1a were positively associated with the age of onset of SCZ in both the dorsolateral prefrontal cortex (DLPFC) and orbitofrontal cortex (OFC). No correlations between the age of onset of SCZ and linear HOMER1 mRNA were observed, whose expression was mostly unaltered in BD and SCZ postmortem brain. Using in vivo circRNA-specific knockdown of circHomer1a in mouse PFC, we show that it modulates the expression of numerous alternative mRNA transcripts from genes involved in synaptic plasticity and psychiatric disease. Intriguingly, in vivo circHomer1a knockdown in mouse OFC resulted in specific deficits in OFCmediated cognitive flexibility. Lastly, we demonstrate that the neuronal RNA-binding protein HuD binds to circHomer1a and can influence its synaptic expression in the frontal cortex. Collectively, our data uncover a novel psychiatric diseaseassociated circRNA that regulates synaptic gene expression and cognitive flexibility.

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Section: In Vivo Ofc Circhomer1a Knockdown Impairs Ofcmediated Behavimentioning

confidence: 99%

A psychiatric disease-related circular RNA controls synaptic gene expression and cognition

et al. 2020

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“…However, research on the biological basis of SZ and other neuropsychiatric disorders has been hampered by the inaccessibility of developing human brains. This problem has been partially circumvented by iPSC technology [22], which allows investigators to grow patient-specific neurons or neuroaggregates [23, 24] for modeling in vitro the cellular developmental abnormalities associated with psychiatric disorders. In the past few years, investigators have successfully applied this strategy and established iPSC lines in a variety of brain disorders including Rett Syndrome, Parkinson Disease, Amyotrophic Lateral Sclerosis, Familial Dysautonomia, and most recently, SZ [25–30].…”

Section: Introductionmentioning

confidence: 99%

Integrative transcriptome network analysis of iPSC-derived neurons from schizophrenia and schizoaffective disorder patients with 22q11.2 deletion

et al. 2016

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BackgroundIndividuals with 22q11.2 Deletion Syndrome (22q11.2 DS) are a specific high-risk group for developing schizophrenia (SZ), schizoaffective disorder (SAD) and autism spectrum disorders (ASD). Several genes in the deleted region have been implicated in the development of SZ, e.g., PRODH and DGCR8. However, the mechanistic connection between these genes and the neuropsychiatric phenotype remains unclear. To elucidate the molecular consequences of 22q11.2 deletion in early neural development, we carried out RNA-seq analysis to investigate gene expression in early differentiating human neurons derived from induced pluripotent stem cells (iPSCs) of 22q11.2 DS SZ and SAD patients.MethodsEight cases (ten iPSC-neuron samples in total including duplicate clones) and seven controls (nine in total including duplicate clones) were subjected to RNA sequencing. Using a systems level analysis, differentially expressed genes/gene-modules and pathway of interests were identified. Lastly, we related our findings from in vitro neuronal cultures to brain development by mapping differentially expressed genes to BrainSpan transcriptomes.ResultsWe observed ~2-fold reduction in expression of almost all genes in the 22q11.2 region in SZ (37 genes reached p-value < 0.05, 36 of which reached a false discovery rate < 0.05). Outside of the deleted region, 745 genes showed significant differences in expression between SZ and control neurons (p < 0.05). Function enrichment and network analysis of the differentially expressed genes uncovered converging evidence on abnormal expression in key functional pathways, such as apoptosis, cell cycle and survival, and MAPK signaling in the SZ and SAD samples. By leveraging transcriptome profiles of normal human brain tissues across human development into adulthood, we showed that the differentially expressed genes converge on a sub-network mediated by CDC45 and the cell cycle, which would be disrupted by the 22q11.2 deletion during embryonic brain development, and another sub-network modulated by PRODH, which could contribute to disruption of brain function during adolescence.ConclusionsThis study has provided evidence for disruption of potential molecular events in SZ patient with 22q11.2 deletion and related our findings from in vitro neuronal cultures to functional perturbations that can occur during brain development in SZ.Electronic supplementary materialThe online version of this article (doi:10.1186/s12918-016-0366-0) contains supplementary material, which is available to authorized users.

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“…Therefore, for each cell type, we analyzed the frequency of each gene included in the identi ed gene sets, and calculated the averaged importance of genes ( Supplementary File 5). disorders, of which HSP70 family has been shown its functions [38], and HSPA1A, a member of HSP70 family, has already been associated with ASD [39]. As to gene CCK (cholecystokinin), it is prioritized in excitatory neurons, which a kind of gut peptide hormones.…”

Section: Cell Typementioning

confidence: 99%

Cell type-specific predictive models for prioritizing genes and gene sets associated with autism spectrum disorder

Guan

Wang

Lin

et al. 2020

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Background Autism spectrum disorder (ASD) is characterized by substantial phenotypic and genetic heterogeneity. Although bulk transcriptomic analyses revealed convergence of disease pathology on common pathways, the brain cell type-specific molecular pathology of ASD is still needed to study. Different gene functions may be dysregulated and causal genes may be distinct among different brain cells in ASD. Gene expression profiling-based machine learning studies can be conducted for the diagnosis of ASD, prioritizing high-confidence gene candidates and promoting the design of effective interventions.Methods To characterize the cell type heterogeneity of ASD and to take advantage of the potential of gene expression signature as diagnostic biomarkers for ASD, we construct multiple kinds of classification models for ASD based on the recently available human brain nucleus gene expression data of ASD and controls. Firstly, we construct cell type-specific predictive models based on individual genes to screen cell type-specific genes associated with ASD. Then from the view of gene set, we construct cell type-specific gene set-based predictive models to screen cell type-specific gene sets associated with ASD. These two kinds of predictive models can be applied to predict the diagnosis of a given nucleus with known cell type. Lastly, we further construct a multi-label predictive model for predicting the cell type and diagnosis of a given nucleus at the same time.Results It is found that the functions of genes with predictive power for ASD are not consistent and the top important genes are distinct among different cells, demonstrating the cell type heterogeneity of ASD. Our findings suggest that layer 2/3 and layer 4 excitatory neurons, layer 5/6 cortico-cortical projection neurons, parvalbumin interneurons, and protoplasmic astrocytes are preferentially affected in ASD. Gene BCYRN1 and CCK are prioritized in excitatory neurons, and HSPA1A is of note in protoplasmic astrocytes.Limitations Our study utilized methods of machine learning to identify biomarkers of ASD, while it is more convincing if subsequent experiments could be conducted to validate the results.Conclusions The results show that it may be feasible to use single cell/nucleus gene expression for ASD detection and the constructed predictive models can promote the diagnosis of ASD. Our analytical pipeline prioritizes ASD-associated cell type-specific genes and gene sets, which may be used as potential biomarkers of ASD.

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Heat Shock Alters the Expression of Schizophrenia and Autism Candidate Genes in an Induced Pluripotent Stem Cell Model of the Human Telencephalon

Cited by 41 publications

References 140 publications

A psychiatric disease-related circular RNA controls synaptic gene expression and cognition

A psychiatric disease-related circular RNA controls synaptic gene expression and cognition

Integrative transcriptome network analysis of iPSC-derived neurons from schizophrenia and schizoaffective disorder patients with 22q11.2 deletion

Cell type-specific predictive models for prioritizing genes and gene sets associated with autism spectrum disorder

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