Cell type-specific dysregulation of gene expression due to Chd8 loss of function during mouse cortical development [scRNA-seq]
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA1141138 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR30015200.fastq.gz | Fastqsanger.gz | |||
| SRR30015300.fastq.gz | Fastqsanger.gz | |||
| SRR30015201.fastq.gz | Fastqsanger.gz | |||
| SRR30015301.fastq.gz | Fastqsanger.gz | |||
| SRR30015202.fastq.gz | Fastqsanger.gz |
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Project description:Disruptive variants in the chromodomain helicase CHD8, which acts as a transcriptional regulator during neurodevelopment, are strongly associated with risk for autism spectrum disorder (ASD). Loss of CHD8 function is hypothesized to perturb gene regulatory networks in the developing brain, thereby contributing to ASD etiology. However, insight into the cell type-specific transcriptional effects of CHD8 loss of function remains limited. We used single-cell and single-nucleus RNA-sequencing to globally profile gene expression and identify dysregulated genes in the embryonic and juvenile wild type and Chd8+/− mouse cortex, respectively. Chd8 and other ASD risk-associated genes showed a convergent expression trajectory that was largely conserved between the mouse and human developing cortex, increasing from the progenitor zones to the cortical plate. Genes associated with risk for neurodevelopmental disorders and genes involved in neuron projection development, chromatin remodeling, signaling, and migration were dysregulated in Chd8+/− embryonic day (E) 12.5 radial glia. Genes implicated in synaptic organization and activity were dysregulated in Chd8+/− postnatal day (P) 25 deep- and upper-layer excitatory neurons, suggesting a delay in synaptic maturation or impaired synaptogenesis due to CHD8 loss of function. Our findings reveal a complex pattern of transcriptional dysregulation in Chd8+/− developing cortex, potentially with distinct biological impacts on progenitors and maturing neurons in the excitatory neuronal lineage.
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Project description:Disruptive variants in the chromodomain helicase CHD8, which acts as a transcriptional regulator during neurodevelopment, are strongly associated with risk for autism spectrum disorder (ASD). Loss of CHD8 function is hypothesized to perturb gene regulatory networks in the developing brain, thereby contributing to ASD etiology. However, insight into the cell type-specific transcriptional effects of CHD8 loss of function remains limited. We used single-cell and single-nucleus RNA-sequencing to globally profile gene expression and identify dysregulated genes in the embryonic and juvenile wild type and Chd8+/− mouse cortex, respectively. Chd8 and other ASD risk-associated genes showed a convergent expression trajectory that was largely conserved between the mouse and human developing cortex, increasing from the progenitor zones to the cortical plate. Genes associated with risk for neurodevelopmental disorders and genes involved in neuron projection development, chromatin remodeling, signaling, and migration were dysregulated in Chd8+/− embryonic day (E) 12.5 radial glia. Genes implicated in synaptic organization and activity were dysregulated in Chd8+/− postnatal day (P) 25 deep- and upper-layer excitatory neurons, suggesting a delay in synaptic maturation or impaired synaptogenesis due to CHD8 loss of function. Our findings reveal a complex pattern of transcriptional dysregulation in Chd8+/− developing cortex, potentially with distinct biological impacts on progenitors and maturing neurons in the excitatory neuronal lineage.
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Project description:Disruptive variants in the chromodomain helicase CHD8, which acts as a transcriptional regulator during neurodevelopment, are strongly associated with risk for autism spectrum disorder (ASD). Loss of CHD8 function is hypothesized to perturb gene regulatory networks in the developing brain, thereby contributing to ASD etiology. However, insight into the cell type-specific transcriptional effects of CHD8 loss of function remains limited. We used single-cell and single-nucleus RNA-sequencing to globally profile gene expression and identify dysregulated genes in the embryonic and juvenile wild type and Chd8+/− mouse cortex, respectively. Chd8 and other ASD risk-associated genes showed a convergent expression trajectory that was largely conserved between the mouse and human developing cortex, increasing from the progenitor zones to the cortical plate. Genes associated with risk for neurodevelopmental disorders and genes involved in neuron projection development, chromatin remodeling, signaling, and migration were dysregulated in Chd8+/− embryonic day (E) 12.5 radial glia. Genes implicated in synaptic organization and activity were dysregulated in Chd8+/− postnatal day (P) 25 deep- and upper-layer excitatory neurons, suggesting a delay in synaptic maturation or impaired synaptogenesis due to CHD8 loss of function. Our findings reveal a complex pattern of transcriptional dysregulation in Chd8+/− developing cortex, potentially with distinct biological impacts on progenitors and maturing neurons in the excitatory neuronal lineage.
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Project description:Cell type-specific dysregulation of gene expression due to Chd8 loss of function during mouse cortical development [snRNA-seq]
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Project description:Cell type-specific dysregulation of gene expression due to Chd8 loss of function during mouse cortical development [bulk RNA-seq]
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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:Whole-exome sequencing studies have implicated chromatin modifiers and transcriptional regulators in autism spectrum disorder (ASD) through the identification of de novo loss of function mutations in affected individuals. Many of these genes are co-expressed in mid-fetal human cortex, suggesting ASD risk genes converge in regulatory networks that are perturbed in ASD during neurodevelopment. To elucidate such networks we mapped promoters and enhancers bound by the chromodomain helicase CHD8, which is strongly enriched in ASD-associated de novo loss of function mutations, using ChIP-seq in mid-fetal human brain, human neural stem cells (hNSCs), and embryonic mouse cortex. We find that CHD8 targets are strongly enriched for ASD risk genes that converge in ASD-associated co-expression networks in human midfetal cortex. CHD8 knockdown in hNSCs results in significant dysregulation of ASD risk genes targeted by CHD8, as well as additional genes important for neurodevelopment, including members of the Wnt/M-NM-2-catenin signaling pathway. Integration of CHD8 binding data with genetic and gene co-expression data in ASD risk models provides support for additional ASD risk genes. Together, our results suggest that loss of CHD8 function contributes to ASD through regulatory perturbation of other ASD risk genes during human cortical development. Two biological replicates for each ChIP with appropriate Input control Four biological replicates for each condition in knockdown experiments (Ctrl construct, Chd8 target C, and Chd8 target G)
2015-01-21 | E-GEOD-57369 | biostudies-arrayexpress
Project description:De novo mutations in CHD8 are strongly associated with autism spectrum disorder (ASD), however the underlying mechanisms remain elusive. Here we report that Chd8 knockdown during cortical development results in defective neural progenitor proliferation and differentiation that ultimately manifests in abnormal neuronal morphology and behaviors in adult mice. Transcriptome analysis revealed that on the one hand Chd8 stimulates the transcription of cell cycle genes, while on the other it precludes the induction of neural specific genes by regulating the expression of PRC2 complex components. Furthermore, knockdown of Chd8 disrupts the expression of key transducers of Wnt signaling, and enhancing Wnt signaling rescues the transcriptional and behavioral deficits caused by Chd8 knockdown. We propose that these roles of Chd8 and the dynamics of its expression during development help negotiate the fine balance between neural progenitor proliferation and differentiation. Together, these observations provide new insights into the etiology of ASD.
2016-09-10 | GSE72442 | GEO
Project description:Chromodomain helicase DNA-binding protein 8 (CHD8), now considered a master transcriptional regulator for autism, is mutated in more autism probands (0.45%) than any other gene. We generated mutant mice with a human loss-of-function (LOF) mutation in Chd8 (Val986X, henceforth referred to as V986*). Heterozygous mutant mice (Chd8V986*/+) display features of ASD, including anxiety like behavior and macrocephaly. Perturbation of CHD8 also recapitulates increased sociability found in other CHD8 mutant animal models. Our study expands previously identified knowledge of CHD8 mutant mouse models by examining temporal alterations in the transcriptional profile of mouse cortical tissue resulting from a reduction in CHD8 expression. Dysregulation of major cellular processes uniquely includes a reduction in neuronal signaling, focal adhesion, and synaptic function genes early in development, that increase in expression into adulthood. At 12 months, heterozygous mice display decreased endoplasmic reticulum (ER) stress, decreased unfolded protein response (UPR) and increased MET signaling likely resulting from a combination of reduced CHD8 expression and reflecting an altered network structure formed early in development. These data provide greater insight into the role of CHD8 in brain function and how mutations in the gene can contribute to ASD etiology.
2020-10-07 | GSE142208 | GEO
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.
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