Human forebrain organoids reveal connections between valproic acid exposure and autism risk

Meng, Qingtuan; Zhang, Wendiao; Wang, Xuan; Jiao, Chuan; Xu, Sheng; Liu, Chun Yu; Tang, Beisha; Chen, Chao

doi:10.1038/s41398-022-01898-x

Cited by 34 publications

(20 citation statements)

References 51 publications

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“…A recent study on non-mature human forebrain organoids treated with VPA for 3 days showed primarily alterations in synaptic transmission and ASD-risk genes which correlates with our own findings 53 . However, in our study, we find that these same genes, in addition to other genes encoding chromatin, transcription, and splicing regulators, display differential transcript usage, which may amplify VPA’s effect on gene expression.…”

Section: Discussionsupporting

confidence: 91%

Dysregulation of The Chromatin Environment Leads to Differential Alternative Splicing as A Mechanism Of Disease In a Human Model of Autism Spectrum Disorders

Leung

Rosenzweig

Yoon

et al. 2022

Preprint

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Autism spectrum disorder (ASD) affects 1 in 44 children. Chromatin regulatory proteins are overrepresented among genes that contain high risk variants in ASD. Disruption of the chromatin environment leads to widespread dysregulation of gene expression, which is traditionally thought as a mechanism of disease pathogenesis associated with ASD. Alternatively, alterations in chromatin dynamics could also lead to dysregulation of alternative splicing, which is understudied as a mechanism of ASD pathogenesis. The anticonvulsant valproic acid (VPA) is a well-known environmental risk factor for ASD that acts as a class I histone deacetylase (HDAC) inhibitor. However, the precise molecular mechanisms underlying defects in human neuronal development associated with exposure to VPA are understudied. To dissect how VPA exposure and subsequent chromatin hyperacetylation influence molecular signatures involved in ASD pathogenesis, we conducted RNA sequencing (RNA-seq) in human cortical neurons that were treated with VPA. We observed that differentially expressed genes (DEGs) were enriched for mRNA splicing, mRNA processing, histone modification, and metabolism related gene sets. Furthermore, we observed widespread increase in the number and the type of alternative splicing events. Analysis of differential transcript usage (DTU) showed that exposure to VPA induces extensive alterations in transcript isoform usage across neurodevelopmentally important genes. Finally, we find that DEGs and genes that display DTU overlap with known ASD-risk genes. Together, these findings suggest that, in addition to differential gene expression, changes in alternative splicing correlated with alterations in the chromatin environment could act as an additional mechanism of disease in ASD.

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Section: Discussionsupporting

confidence: 91%

Dysregulation of The Chromatin Environment Leads to Differential Alternative Splicing as A Mechanism Of Disease In a Human Model of Autism Spectrum Disorders

Leung

Rosenzweig

Yoon

et al. 2022

Preprint

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“…The U2F hiPSCs was obtained from the Cellapy Technology (Beijing, China), and the ACS-1011 was obtained from the American type culture collection (ATCC). Pluripotency and karyotype of U2F hiPSCs were con rmed by immuno uorescence and karyotype analysis as shown in our previous studies 46, 47 . The hiPSCs were cultured in Matrigel (Corning, 354277)-coated plate and supplemented with the mTeSR Plus medium (STEMCELL Technologies, 05825) and 1% penicillin/streptomycin (Gibco, 10378016).…”

Section: Cell Culturementioning

confidence: 53%

“…From day 43, organoids were cultured in the Forebrain Organoid Maintenance Medium. hFOs were characterized using immunostaining as described in our previous studies 46, 47 .…”

Section: Generation Of Hfosmentioning

confidence: 99%

Human forebrain organoids-based multi-omics analyses reveal PCCB's regulation on GABAergic system contributing to schizophrenia

Zhang

et al. 2023

Preprint

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Identifying genes whose expression is associated with schizophrenia (SCZ) risk by transcriptome-wide association studies (TWAS) facilitates downstream experimental studies. Here, we integrated multiple published datasets of TWAS (including FUSION, PrediXcan, summary-data-based Mendelian randomization (SMR), joint-tissue imputation approach with Mendelian randomization (MR-JTI)), gene coexpression, and differential gene expression analysis to prioritize SCZ candidate genes for functional study. Convergent evidence prioritized Propionyl-CoA Carboxylase Subunit Beta (PCCB), a nuclear-encoded mitochondrial gene, as an SCZ risk gene. However, the PCCB’s contribution to SCZ risk has not been investigated before. Using dual luciferase reporter assay, we identified that SCZ-associated SNP rs35874192, an eQTL SNP for PCCB, showed differential allelic effects on transcriptional activities. PCCB knockdown in human forebrain organoids (hFOs) followed by RNA-seq revealed dysregulation of genes enriched with multiple neuronal functions including gamma-aminobutyric acid (GABA)-ergic synapse, as well as genes dysregulated in postmortem brains of SCZ patients or in cerebral organoids derived from SCZ patients. The metabolomic and mitochondrial function analyses confirmed the deceased GABA levels resulted from reduced tricarboxylic acid cycle in PCCB knockdown hFOs. Multielectrode array recording analysis showed that PCCB knockdown in hFOs resulted into SCZ-related phenotypes including hyper-neuroactivities and decreased synchronization of neural network. In summary, this study utilized hFOs-based multi-omics data and revealed that PCCB downregulation may contribute to SCZ risk through regulating GABAergic system, highlighting the mitochondrial function in SCZ.

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“…One recent study has found that VPA exposure in human forebrain organoids caused altered many ASD risk gene expression ( Meng et al, 2022 ). Consistent with this, organoid RNA sequencing displayed that VPA treatment changed the levels of ASD risk genes, which overlapped with aberrant genes in ASD brains and patient-derived brain organoids.…”

Section: Discussionmentioning

confidence: 99%

Valproic acid exposure decreases neurogenic potential of outer radial glia in human brain organoids

Zang

Yin

et al. 2022

Front. Mol. Neurosci.

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Valproic acid (VPA) exposure during pregnancy leads to a higher risk of autism spectrum disorder (ASD) susceptibility in offspring. Human dorsal forebrain organoids were used to recapitulate course of cortical neurogenesis in the developing human brain. Combining morphological characterization with massive parallel RNA sequencing (RNA-seq) on organoids to analyze the pathogenic effects caused by VPA exposure and critical signaling pathway. We found that VPA exposure in organoids caused a reduction in the size and impairment in the proliferation and expansion of neural progenitor cells (NPCs) in a dose-dependent manner. VPA exposure typically decreased the production of outer radial glia-like cells (oRGs), a subtype of NPCs contributing to mammalian neocortical expansion and delayed their fate toward upper-layer neurons. Transcriptomics analysis revealed that VPA exposure influenced ASD risk gene expression in organoids, which markedly overlapped with irregulated genes in brains or organoids originating from ASD patients. We also identified that VPA-mediated Wnt/β-catenin signaling pathway activation is essential for sustaining cortical neurogenesis and oRGs output. Taken together, our study establishes the use of dorsal forebrain organoids as an effective platform for modeling VPA-induced teratogenic pathways involved in the cortical neurogenesis and oRGs output, which might contribute to ASD pathogenesis in the developing brain.

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Human forebrain organoids reveal connections between valproic acid exposure and autism risk

Cited by 34 publications

References 51 publications

Dysregulation of The Chromatin Environment Leads to Differential Alternative Splicing as A Mechanism Of Disease In a Human Model of Autism Spectrum Disorders

Dysregulation of The Chromatin Environment Leads to Differential Alternative Splicing as A Mechanism Of Disease In a Human Model of Autism Spectrum Disorders

Human forebrain organoids-based multi-omics analyses reveal PCCB's regulation on GABAergic system contributing to schizophrenia

Valproic acid exposure decreases neurogenic potential of outer radial glia in human brain organoids

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