Genotype-phenotype-epiphenotype analysis to decipher severity, penetrance, pleiotropy and mechanisms in CHD8-related neurodevelopmental disorder
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA1148667 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR30260591.fastq.gz | Fastqsanger.gz | |||
| SRR30260592.fastq.gz | Fastqsanger.gz | |||
| SRR30260593.fastq.gz | Fastqsanger.gz | |||
| SRR30260594.fastq.gz | Fastqsanger.gz | |||
| SRR30260595.fastq.gz | Fastqsanger.gz |
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Project description:Peripheral blood DNA methylation (DNAm)-based episignature analysis has emerged as an important diagnostic tool. We analysed the relationship between variant type/severity, clinical phenotypes, and epiphenotypes in a cohort of individuals with rare CHD8 variants. Furthermore, we performed DNAm studies in Chd8+/- mouse neocortex to comparatively assess the effect of CHD8 loss-of-function on DNA methylome in a cross-species, cross-tissue manner.
2024-08-16 | GSE274977 | GEO
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:Mutations in the gene encoding the chromodomain helicase DNA-binding protein 8 (CHD8) are strongly associated with autism spectrum disorder (ASD). Although duplications of the locus spanning CHD8 are also found in individuals with neurodevelopmental disorders, the role of CHD8 duplication in clinical phenotypes and the underlying mechanisms have remained unknown. Here we show that mice with Chd8 overexpression modeling human CHD8 duplication manifest growth retardation, microcephaly, and behavioral abnormalities including hyperactivity and reduced anxiety-like behavior. Chd8 overexpression results in alterations of transcription and chromatin accessibility of genes involved in neurogenesis that are associated with aberrant binding of CHD8 to enhancer regions and impairs differentiation of deep-layer neurons. Furthermore, genetic and pharmacological interventions rescue hyperactive behavior of Chd8 overexpression mice. Our results thus indicate that Chd8 overexpression mice recapitulate key features of CHD8 duplication syndrome, and they provide insight into cellular and molecular pathogenesis underlying neurodevelopmental disorders.
2025-04-05 | GSE263334 | GEO
Project description:Mutations in the gene encoding the chromodomain helicase DNA-binding protein 8 (CHD8) are strongly associated with autism spectrum disorder (ASD). Although duplications of the locus spanning CHD8 are also found in individuals with neurodevelopmental disorders, the role of CHD8 duplication in clinical phenotypes and the underlying mechanisms have remained unknown. Here we show that mice with Chd8 overexpression modeling human CHD8 duplication manifest growth retardation, microcephaly, and behavioral abnormalities including hyperactivity and reduced anxiety-like behavior. Chd8 overexpression results in alterations of transcription and chromatin accessibility of genes involved in neurogenesis that are associated with aberrant binding of CHD8 to enhancer regions and impairs differentiation of deep-layer neurons. Furthermore, genetic and pharmacological interventions rescue hyperactive behavior of Chd8 overexpression mice. Our results thus indicate that Chd8 overexpression mice recapitulate key features of CHD8 duplication syndrome, and they provide insight into cellular and molecular pathogenesis underlying neurodevelopmental disorders.
2025-04-05 | GSE288732 | GEO
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.
2014-10-07 | GSE61491 | GEO
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.
2014-10-07 | GSE61487 | GEO
Project description:We examined the impact of germline heterozygous frameshift Chd8 mutation on neurodevelopment in mice. Adult Chd8+/del5 mice exhibited cognitive impairment correlated with increased cerebral cortex, hippocampus, and amygdala volume, but displayed normal social interactions and no repetitive behaviors. Network analysis of neurodevelopmental gene expression revealed widespread transcriptional changes in Chd8+/del5 mice across pathways disrupted in neurodevelopmental disorders, including neurogenesis, synaptic processes, and neuroimmune signaling. Among gene co-expression networks, we identified a module with peak expression in early brain development that featured dysregulation of genes enriched for promoter binding by Chd8 and associated with RNA processing, chromatin remodeling, and cell cycle. We validated increased neuronal proliferation and splicing alterations during Chd8+/del5 brain development. Our results show that Chd8+/del5 mice exhibit neurodevelopmental changes paralleling humans with CHD8 mutations and highlight widespread pathological consequences of Chd8 haploinsufficiency.
2017-06-21 | GSE99331 | 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
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, β-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
Project description:Loss-of-function mutations in the chromodomain helicase DNA-binding 8 (CHD8) gene are strongly associated with Autism Spectrum Disorders (ASD). Indeed, the reduction of CHD8 causes transcriptional, epigenetic and cellular phenotypic changes, correlated to disease that can be monitored in assessing new therapeutic approaches. SINEUPs are a functional class of natural and synthetic antisense long non-coding RNAs able to stimulate the translation of antisense target mRNA, with no effect on transcription. Here we employed synthetic SINEUP-CHD8 targeting the first and third AUG of the CHD8 coding sequence to efficiently stimulate endogenous CHD8 protein production. SINEUP-CHD8 were effective in cells with reduced levels of the target protein and in patients’-derived fibroblasts with CHD8 mutations. Functionally, SINEUP-CHD8 were able to revert molecular phenotypes associated with CHD8-suppression, i.e. genome-wide transcriptional dysregulation, and the reduction of H3K36me3 levels. Strikingly, in chd8-morpholino-treated and ENU mutant zebrafish embryos, SINEUP-chd8 injection confirmed the ability of SINEUP RNA to rescue the chd8-suppression-induced macrocephaly phenotype and neuronal hyperproliferation. Thus, SINEUP-CHD8 molecule(s) represent a proof-of-concept towards the development of a novel RNA-based therapy for neurodevelopmental syndromes with implications for, and beyond ASD, and relevant to genetic disorders caused by protein haploinsufficiency.
2025-02-24 | PXD056482 | Pride