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Cell type-specific dysregulation of gene expression due to Chd8 loss of function during mouse cortical development [snRNA-seq]

ABSTRACT: 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.

ORGANISM(S): Mus musculus

PROVIDER: GSE273765 | GEO | 2024/08/14

REPOSITORIES: GEO

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Cell type-specific dysregulation of gene expression due to Chd8 loss of function during mouse cortical development [scRNA-seq]

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.

2024-08-14 | GSE273271 | GEO

Cell type-specific dysregulation of gene expression due to Chd8 loss of function during mouse cortical development [bulk RNA-seq]

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The chromatin modifier CHD8 targets autism risk genes during human neurodevelopmentM-BM-

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

The chromatin modifier CHD8 targets autism risk genes during human neurodevelopment

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/β-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.

2015-01-21 | GSE57369 | GEO

Transcriptome of iPSC-derived Neural Cells with Heterozygous Knockout in CHD8

Project description:CHD8, encoding Chromodomain helicase DNA binding protein 8, is a top autism spectrum disorders (ASDs) risk gene. To better understanding the molecular links between CHD8 functions and ASD, we have applied the CRISPR/Cas9 technology to knockout one copy of CHD8 in induced pluripotent stem cells (iPSCs) to mimic the loss of function status that would exist in the developing human embryo prior to neuronal differentiation. Transcriptome profiling (RNA-seq) in neural progenitors and early differentiating neurons revealed that CHD8 hemizygosity (CHD8+/-) affected the expression of several thousands of genes, enriched for functions of neural development, Î²-catenin/Wnt signaling, extracellular matrix, and skeletal system development. Moreover, CHD8 regulates multiple genes implicated in ASD, schizophrenia and genes associated with brain volume. iPSCs derived from a healthy subject were transduced with CRISPR/Cas9 vectors with single guide RNA sequences to target the N-terminal of CHD8 protein to generate truncated mutation seach of the two target sequences. Two clones, one with a 2-bp (KO1) and the other with a 10-bp (KO2) heterozygous deletion were found.The CHD8+/- iPSC lines were used to generate NPCs and early differentiating neurons for RNA-seq analysis, together with samples prepared from the parental clones, for a total of 8 samples (two biological replicates of wild-type (WT) and CHD8+/- at two neurodevelopmental stages).

2015-11-05 | E-GEOD-71594 | biostudies-arrayexpress

Transcriptome of iPSC-derived Neural Cells with Heterozygous Knockout in CHD8

2015-11-05 | GSE71594 | GEO

Transcriptome of iPSC-derived Cerebral Organoids with Heterozygous Knockout in CHD8

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.

2017-02-16 | GSE85417 | GEO

CHD8 haploinsufficiency alters the developmental trajectories of human excitatory and inhibitory neurons linking autism phenotypes with transient cellular defects

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

Transcriptome analysis of Chd8 S62X heterozygote mutant and wild-type mice

Project description:Autism spectrum disorders (ASD) are ~4-times more common in males than females, and CHD8 (a chromatin remodeler)-related ASD shows a strong male bias (~5:1), although the underlying mechanism remains unclear. Chd8-mutant mice with a C-terminal protein-truncating mutation (N2373X) display male-preponderant behavioral deficits as juveniles and adults, although whether this also applies to other Chd8 mutations remains unknown. Here we report that new Chd8-mutant mice with a stronger N-terminal protein-truncating mutation (S62X) display male-preponderant autistic-like behaviors at juvenile stages, but as adults, both males and females share behavioral deficits. Excitatory synaptic transmission is suppressed and enhanced in male and female juvenile Chd8+/S62X mice, respectively, but similarly enhanced in adults. ASD-like transcriptomic changes occur monophasically in newborn and juvenile (but not adult) males but biphasically in newborn and adult (not juvenile) females. Therefore, a strong CHD8 mutation induces early-onset ASD-like phenotypes in males but late-onset phenotypes in females after juvenile-stage female protection.

2023-03-08 | GSE167053 | GEO

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Project description:Shank2 is an abundant excitatory postsynaptic scaffolding protein implicated in neurodevelopmental disorders, including autism spectrum disorders (ASD), intellectual disability, developmental delay, and schizophrenia. Shank2-mutant mice with a homozygous deletion of exons 6 and 7 (Shank2-HM mice) show ASD-like behavioral deficits and altered synaptic functions, although little is known about how different brain regions contribute to Shank2-mutant phenotypes. Here we attempted transcriptomic analyses of the prefrontal cortex, hippocampus, and striatum in adult Shank2-heterozygous/HT and Shank2-homozygous/HM mice. The mutant cortex, hippocampus, and striatum displayed distinct sets of differentially expressed genes associated with neuronal and synaptic functions in a gene dosage-differential manner. Gene set enrichment analyses of cortical Shank2-HT transcripts revealed increased synaptic gene expression and transcriptomic changes that are opposite to those observed in ASD (reverse-ASD), whereas cortical Shank2-HM transcripts displayed decreased synaptic gene expression and ASD-like transcriptomic patterns. The hippocampal Shank2-HT transcripts displayed minimally altered synaptic gene expression and mixed ASD-like and reverse-ASD patterns, whereas the Shank2-HM-hippocampus showed increased synaptic gene expression and reverse-ASD patterns. The striatal Shank2-HT/HM transcriptomes were largely similar to the hippocampal transcriptomes, although the main changes were observed in cell-type-specific genes, unlike the hippocampal changes mainly involving ASD-related/risk genes. These results indicate that heterozygous and homozygous Shank2 deletions in mice lead to brain region- and gene dosage-differential transcriptomic changes.

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