Bulk RNA-seq of cerebral organoids investigating the role of CHD8 in cortical development
Ontology highlight
ABSTRACT:
PROVIDER: PRJEB42177 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| ERR5011850.fastq.gz | Fastqsanger.gz | |||
| ERR5011860.fastq.gz | Fastqsanger.gz | |||
| ERR5011851.fastq.gz | Fastqsanger.gz | |||
| ERR5011852.fastq.gz | Fastqsanger.gz | |||
| ERR5011853.fastq.gz | Fastqsanger.gz |
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Project description:We used cerebral organoids generated from wildtype and CHD8 +/- human ES cells to study the effects of CHD8, one of the top ASD risk genes, on early cortical development. CHD8 +/- hESC were generated using the CRISPR/Cas9 system to create a deletion within the helicase domain. Cerebral organoids were generated according to the protocol from Lancaster et al 2013 with minor modifications.
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Project description:Bulk RNA-seq of cerebral organoids investigating the role of CHD8 in cortical development
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Project description:Chromodomain helicase DNA-binding 8 (CHD8) is one of the most frequently mutated genes causative of autism spectrum disorder (ASD). While its phenotypic spectrum often encompasses macrocephaly and hence implicates cortical abnormalities in this form of ASD, the neurodevelopmental impact of human CHD8 haploinsufficiency remains unexplored. Here we combined human cerebral organoids and single cell transcriptomics to define the effect of ASD-linked CHD8 mutations on human cortical development. We found that CHD8 haploinsufficiency causes a major disruption of neurodevelopmental trajectories with an accelerated generation of inhibitory neurons and a delayed production of excitatory neurons alongside the ensuing protraction of the proliferation phase. This imbalance may contribute to the significant enlargement of cerebral organoids in line with the macrocephaly observed in patients with CHD8 mutations. By adopting an isogenic design of patient-specific mutations and mosaic cerebral organoids, we define genotype-phenotype relationships and uncover their cell-autonomous nature. Finally, our results assign different CHD8-dependent molecular defects to particular cell types, pointing to an abnormal and extended program of proliferation and alternative splicing specifically affected in, respectively, the radial glial and immature neuronal compartments. By identifying temporally restricted cell-type specific effects of human CHD8 mutations, our study uncovers developmental alterations as reproducible endophenotypes for neurodevelopmental disease modelling.
2024-01-27 | E-MTAB-11406 | biostudies-arrayexpress
Project description:CHD8 (chromodomain helicase DNA binding protein 8), which codes for a member of the CHD family of ATP-dependent chromatin-remodeling factors, is the most commonly mutated gene in autism spectrum disorders (ASD) identified in exome-sequencing studies. Loss of function mutations in the gene have also been found in schizophrenia (SZ) and intellectual disabilities, and affects cancer cell proliferation. To better understanding the molecular links between CHD8 functions and ASD, we have applied the CRISPR/Cas9 technology to knockout (KO) one copy of CHD8 in induced pluripotent stem cells (iPSCs) and build cerebral organoids, a model for the developing telencephalon. RNA-seq was carried out on KO organoids (CHD8+/-) and isogenic controls (CHD8+/+). Differentially expressed genes (DEGs) revealed an enrichment of genes involved in neurogenesis, forebrain development, Wnt/β-catenin signaling and axonal guidance. The SZ and bipolar disorder (BD) candidate gene TCF4 was significantly upregulated. Our CHD8 KO DEGs were significantly overlapped with those found in a transcriptome analysis using cerebral organoids derived from a family with idiopathic ASD and another transcriptome study using iPS cell-derived neurons from patients with BD, a condition characterized in a subgroup of patients by dysregulated WNT/β-catenin signaling. Overall, the findings show that distinct ASD, SZ and BD candidate genes converge on common molecular targets - an important consideration for developing novel therapeutics in genetically heterogeneous complex traits.
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Project description:Cerebral organoids â three-dimensional cultures of human cerebral tissue derived from pluripotent stem cells â have emerged as models of human cortical development. However, the extent to which in vitro organoid systems recapitulate neural progenitor cell proliferation and neuronal differentiation programs observed in vivo remains unclear. Here we use single-cell RNA sequencing (scRNA-seq) to dissect and compare cell composition and progenitor-to-neuron lineage relationships in human cerebral organoids and fetal neocortex. Covariation network analysis using the fetal neocortex data reveals known and novel interactions among genes central to neural progenitor proliferation and neuronal differentiation. In the organoid, we detect diverse progenitors and differentiated cell types of neuronal and mesenchymal lineages, and identify cells that derived from regions resembling the fetal neocortex. We find that these organoid cortical cells use gene expression programs remarkably similar to those of the fetal tissue in order to organize into cerebral cortex-like regions. Our comparison of in vivo and in vitro cortical single cell transcriptomes illuminates the genetic features underlying human cortical development that can be studied in organoid cultures. 734 single-cell transcriptomes from human fetal neocortex or human cerebral organoids from multiple time points were analyzed in this study. All single cell samples were processed on the microfluidic Fluidigm C1 platform and contain 92 external RNA spike-ins. Fetal neocortex data were generated at 12 weeks post conception (chip 1: 81 cells; chip 2: 83 cells) and 13 weeks post conception (62 cells). Cerebral organoid data were generated from dissociated whole organoids derived from induced pluripotent stem cell line 409B2 (iPSC 409B2) at 33 days (40 cells), 35 days (68 cells), 37 days (71 cells), 41 days (74 cells), and 65 days (80 cells) after the start of embryoid body culture. Cerebral organoid data were also generated from microdissected cortical-like regions from H9 embryonic stem cell derived organoids at 53 days (region 1, 48 cells; region 2, 48 cells) or from iPSC 409B2 organoids at 58 days (region 3, 43 cells; region 4, 36 cells).
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Project description:Pluripotent stem cells (PSC) can differentiate inot any cell type of an organism. Their remarkable capability of self-organization enables the formation of three-dimensional structures that resembles miniature organs, including cerebral organoids. These organoids can recreate early steps of the human cerebral cortex development, and show great potential for modeling human diseases, particularly for those with a developmental component. This data evidences stem cell-derived cerebral organoids as a key model to study brain development and neurodevelopmental, neurodegenerative and neuropsychiatric diseases.
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Project description:We developed a human cerebral organoid model derived from induced pluripotent stem cells (iPSCs) with targeted genome editing to abolish protein expression of the Contactin Associated Protein-like 2 (CNTNAP2) autism spectrum disorder (ASD) risk gene, mimicking loss-of-function mutations seen in patients. CNTNAP2-/- cerebral organoids displayed accelerated cell cycle, ventricular zone disorganisation and increased cortical folding. Proteomic analysis revealed disruptions in glutamatergic/GABAergic synaptic pathways and neurodevelopment, highlighting increased protein expression of corticogenesis and neurodevelopment-related genes such as Forkhead box protein G1 (FOXG1) and Paired box 6 (PAX6). Transcriptomic analysis revealed differentially expressed genes (DEG) belonging to inhibitory neuron-related gene networks. Interestingly, there was a weak correlation between the transcriptomic and proteomic data, suggesting nuanced translational control mechanisms. Along these lines we find upregulated Protein Kinase B (Akt)/mechanistic target of rapamycin (mTOR) signalling in CNTNAP2-/- organoids. Spatial transcriptomics analysis of CNTNAP2-/- ventricular zones demonstrated pervasive changes in gene expression, particularly in PAX6- cells, implicating upregulation of cell cycle regulation pathways, synaptic and glutamatergic/GABAergic pathways. We noted a significant overlap of all omics datasets with idiopathic ASD (macrocephaly) iPSC-derived telencephalic organoids DEG, where FOXG1 was upregulated, along with aberrant expression of Glutamate decarboxylase 1 (GAD1) and T-Box Brain Transcription Factor 1 (TBR1), suggesting altered GABAergic/glutamatergic neuron development. These findings potentially highlight a shared mechanism in the early cortical development of various forms of ASD, further elucidate the role of CNTNAP2 in ASD pathophysiology and cortical development and pave the way for targeted therapies using cerebral organoids as preclinical models.
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Project description:Cerebral organoids – three-dimensional cultures of human cerebral tissue derived from pluripotent stem cells – have emerged as models of human cortical development. However, the extent to which in vitro organoid systems recapitulate neural progenitor cell proliferation and neuronal differentiation programs observed in vivo remains unclear. Here we use single-cell RNA sequencing (scRNA-seq) to dissect and compare cell composition and progenitor-to-neuron lineage relationships in human cerebral organoids and fetal neocortex. Covariation network analysis using the fetal neocortex data reveals known and novel interactions among genes central to neural progenitor proliferation and neuronal differentiation. In the organoid, we detect diverse progenitors and differentiated cell types of neuronal and mesenchymal lineages, and identify cells that derived from regions resembling the fetal neocortex. We find that these organoid cortical cells use gene expression programs remarkably similar to those of the fetal tissue in order to organize into cerebral cortex-like regions. Our comparison of in vivo and in vitro cortical single cell transcriptomes illuminates the genetic features underlying human cortical development that can be studied in organoid cultures.
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