Loss of autism-candidate CHD8 perturbs neural crest development and intestinal homeostatic balance [RNA-seq]
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ABSTRACT:
PROVIDER: PRJNA764215 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR15931300.fastq.gz | Fastqsanger.gz | |||
| SRR15931293.fastq.gz | Fastqsanger.gz | |||
| SRR15931294.fastq.gz | Fastqsanger.gz | |||
| SRR15931295.fastq.gz | Fastqsanger.gz | |||
| SRR15931296.fastq.gz | Fastqsanger.gz |
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Project description:Loss of autism-candidate CHD8 perturbs neural crest development and intestinal homeostatic balance
| PRJNA764218 | ENA
Project description:Loss of autism-candidate CHD8 perturbs neural crest development and intestinal homeostatic balance [scRNA-seq]
| PRJNA764222 | ENA
Project description:Individuals with mutations in CHD8 present with gastrointestinal complaints, yet the underlying mechanisms are understudied. Here, utilizing a stable constitutive chd8 mutant zebrafish model, we found that the loss of chd8 leads to reduced number of vagal neural crest cells (NCCs), enteric neural and glial progenitors, emigrating from the neural tube and that their early migration capability was altered. At later stages, although the intestinal colonization by the NCCs was complete, we found decreased numbers of both serotonin-producing enterochromaffin cells and NCC-derived serotonergic neurons, suggesting an intestinal hyposerotonemia in absence of chd8. Further, transcriptomic analyses revealed altered expression of key receptors and enzymes in serotonin and acetylcholine signaling pathways. Tissue examination of chd8 mutants revealed thinner intestinal epithelium accompanied by accumulation of neutrophils and decreased numbers of goblet cells and eosinophils. Last, single-cell sequencing of whole intestines showed a global disruption of the immune balance with perturbed expression of inflammatory interleukins and changes in immune cell clusters. Our findings propose a causal developmental link between chd8, NCC development, intestinal homeostasis, and autism-associated gastrointestinal complaints.
2022-10-21 | GSE184359 | GEO
Project description:Individuals with mutations in CHD8 present with gastrointestinal complaints, yet the underlying mechanisms are understudied. Here, utilizing a stable constitutive chd8 mutant zebrafish model, we found that the loss of chd8 leads to reduced number of vagal neural crest cells (NCCs), enteric neural and glial progenitors, emigrating from the neural tube and that their early migration capability was altered. At later stages, although the intestinal colonization by the NCCs was complete, we found decreased numbers of both serotonin-producing enterochromaffin cells and NCC-derived serotonergic neurons, suggesting an intestinal hyposerotonemia in absence of chd8. Further, transcriptomic analyses revealed altered expression of key receptors and enzymes in serotonin and acetylcholine signaling pathways. Tissue examination of chd8 mutants revealed thinner intestinal epithelium accompanied by accumulation of neutrophils and decreased numbers of goblet cells and eosinophils. Last, single-cell sequencing of whole intestines showed a global disruption of the immune balance with perturbed expression of inflammatory interleukins and changes in immune cell clusters. Our findings propose a causal developmental link between chd8, NCC development, intestinal homeostasis, and autism-associated gastrointestinal complaints.
2022-10-21 | GSE184363 | GEO
Project description:Individuals with mutations in CHD8 present with gastrointestinal complaints, yet the underlying mechanisms are understudied. Here, using a stable constitutive chd8 mutant zebrafish model, we found that the loss of chd8 leads to a reduced number of vagal neural crest cells (NCCs), enteric neural and glial progenitors, emigrating from the neural tube, and that their early migration capability was altered. At later stages, although the intestinal colonization by NCCs was complete, we found the decreased numbers of both serotonin-producing enterochromaffin cells and NCC-derived serotonergic neurons, suggesting an intestinal hyposerotonemia in the absence of chd8 Furthermore, transcriptomic analyses revealed an altered expression of key receptors and enzymes in serotonin and acetylcholine signaling pathways. The tissue examination of chd8 mutants revealed a thinner intestinal epithelium accompanied by an accumulation of neutrophils and the decreased numbers of goblet cells and eosinophils. Last, single-cell sequencing of whole intestines showed a global disruption of the immune balance with a perturbed expression of inflammatory interleukins and changes in immune cell clusters. Our findings propose a causal developmental link between chd8, NCC development, intestinal homeostasis, and autism-associated gastrointestinal complaints.
| S-EPMC9664244 | biostudies-literature
Project description:This SuperSeries is composed of the SubSeries listed below.
2022-10-21 | GSE184364 | GEO
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:Truncating mutations of CHD8, encoding a chromodomain helicase, and of many other genes with diverse functions, are strong-effect risk factors for autism spectrum disorder (ASD), suggesting multiple mechanisms of pathogenesis. We explored the transcriptional networks that CHD8 regulates in neural progenitor cells (NPCs) by reducing its expression and then integrating transcriptome sequencing (RNA-seq) with genome-wide CHD8 binding (ChIP-seq). Suppressing CHD8 to levels comparable with loss of a single allele caused altered expression of 1,756 genes, 64.9% of which were up-regulated. CHD8 showed widespread binding to chromatin, with 7,324 replicated sites that marked 5,658 genes. Integration of these data suggests that a limited array of direct regulatory effects of CHD8 produced a much larger network of secondary expression changes. Genes indirectly down-regulated (i.e., without CHD8 binding sites) reflect pathways involved in brain development, including synapse formation, neuron differentiation, cell adhesion, and axon guidance, whereas CHD8-bound genes are strongly associated with chromatin modification and transcriptional regulation. Genes associated with ASD were strongly enriched among indirectly down-regulated loci (p = 1.01x10-9) and CHD8-bound genes (p = 4.34x10-3), which align with previously identified co-expression modules during fetal development. We also find an intriguing enrichment of cancer related gene-sets among CHD8-bound genes (p < 1.9x10-11). In vivo suppression of chd8 in zebrafish produced macrocephaly comparable to that of humans with inactivating mutations. These data indicate that heterozygous disruption of CHD8 precipitates a network of gene expression changes involved in neurodevelopmental pathways in which many ASD-associated genes may converge on shared mechanisms of pathogenesis. RNA-seq in NPCs treated with shRNAs targeting CHD8. For controls, NPCs were treated with shRNAs targeting GFP and LacZ. Infection and sequencing was carried out in two separate batches, with one GFP and one LacZ sample in each batch. All samples were sequenced in two technical replicates.
2014-10-07 | E-GEOD-61491 | biostudies-arrayexpress
Project description:CHD8 is an ATP-dependent chromatin-remodeling factor encoded by the most frequently mutated gene in individuals with autism spectrum disorder (ASD). Although many studies have examined the consequences of CHD8 haploinsufficiency in cells and mice, few have focused on missense mutations, the most common type of CHD8 alteration in ASD patients. We here characterized CHD8 missense mutations in ASD patients according to six prediction scores and experimentally examined the effects of such mutations on the biochemical activities of CHD8, neural differentiation of embryonic stem cells, and mouse behavior. Only mutations with high prediction scores gave rise to ASD-like phenotypes in mice, suggesting that not all CHD8 missense mutations detected in ASD patients are directly responsible for the development of ASD. Furthermore, we found that mutations with high scores cause ASD by mechanisms either dependent on or independent of loss of chromatin-remodeling function. Our results thus provide insight into the molecular underpinnings of ASD pathogenesis caused by missense mutations of CHD8.
2024-02-28 | GSE227579 | 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.
2024-01-27 | E-MTAB-11406 | biostudies-arrayexpress