Chd8 haploinsufficiency impairs early brain development and impacts protein homeostasis later in life
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ABSTRACT:
PROVIDER: PRJNA596222 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR10721100_1.fastq.gz | Fastqsanger.gz | |||
| SRR10721100_2.fastq.gz | Fastqsanger.gz | |||
| SRR10721101_1.fastq.gz | Fastqsanger.gz | |||
| SRR10721101_2.fastq.gz | Fastqsanger.gz | |||
| SRR10721102_1.fastq.gz | Fastqsanger.gz |
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Similar Datasets
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:BackgroundChromodomain helicase DNA-binding protein 8 (Chd8) is a high-confidence risk gene for autism spectrum disorder (ASD). However, how Chd8 haploinsufficiency impairs gene expression in the brain and impacts behavior at different stages of life is unknown.MethodsWe generated a mutant mouse line with an ASD-linked loss-of-function mutation in Chd8 (V986*; stop codon mutation). We examined the behavior of Chd8 mutant mice along with transcriptional changes in the cerebral cortex as a function of age, with a focus on one embryonic (E14.5) and three postnatal ages (1, 6, and 12 months).ResultsChd8V986*/+ mutant mice displayed macrocephaly, reduced rearing responses and reduced center time in the open field, and enhanced social novelty preference. Behavioral phenotypes were more evident in Chd8V986*/+ mutant mice at 1 year of age. Pup survival was reduced in wild-type x Chd8V986*/+ crosses when the mutant parent was female. Transcriptomic analyses indicated that pathways associated with synaptic and neuronal projections and sodium channel activity were reduced in the cortex of embryonic Chd8V986*/+ mice and then equalized relative to wild-type mice in the postnatal period. At 12 months of age, expression of genes associated with endoplasmic reticulum (ER) stress, chaperone-mediated protein folding, and the unfolded protein response (UPR) were reduced in Chd8V986*/+ mice, whereas genes associated with the c-MET signaling pathway were increased in expression.LimitationsIt is unclear whether the transcriptional changes observed with age in Chd8V986*/+ mice reflect a direct effect of CHD8-regulated gene expression, or if CHD8 indirectly affects the expression of UPR/ER stress genes in adult mice as a consequence of neurodevelopmental abnormalities.ConclusionsCollectively, these data suggest that UPR/ER stress pathways are reduced in the cerebral cortex of aged Chd8V986*/+ mice. Our study uncovers neurodevelopmental and age-related phenotypes in Chd8V986*/+ mice and highlights the importance of controlling for age when studying Chd8 haploinsufficient mice.
| S-EPMC7537101 | biostudies-literature
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:IRF4 Haploinsufficiency Impairs Affinity Maturation
| PRJNA767888 | ENA
Project description:CHD8 is a putative chromatin remodeling ATPase of the SNF2 family. We found that depletion of CHD8 impairs cell proliferation. In order to identify CHD8 target genes, we performed a transcriptomic analysis of CHD8-depleted cells. CHD8 was knockdown by doxycyclin-dependent expression of a shRNA that target the CHD8 mRNA. Experiment Overall Design: C33KD2 is a stable cell line where expression of a shRNA, that targets the CHD8 mRNA, is dependent on doxycycline. Addition of doxyclycin provokes a significant reduction in the level of CHD8 protein. Total RNA samples coming from C33KD2 cells cultured for 48 hours either with or without 2 µg/ml doxycycline were used to generate complementary RNA labelled with Cy5 with the Agilent Low RNA Input Fluorescent Linear Amplification Kit (Agilent Technologies). The reference sample was Stratagene human universal reference and was amplified at the same time as the sample RNA using the same method. Reference samples were labeled using Cy3.
2009-05-14 | E-GEOD-11422 | biostudies-arrayexpress
Project description:CHD8 is a putative chromatin remodeling ATPase of the SNF2 family. We found that depletion of CHD8 impairs cell proliferation. In order to identify CHD8 target genes, we performed a transcriptomic analysis of CHD8-depleted cells. CHD8 was knockdown by doxycyclin-dependent expression of a shRNA that target the CHD8 mRNA. Keywords: CHD8 knockdown analysis
2009-05-01 | GSE11422 | GEO
Project description:Disruptive mutations in the chromodomain helicase DNA binding protein 8 (CHD8) have been recurrently associated with Autism Spectrum Disorders (ASD). Here we investigated how chromatin reacts to CHD8 suppression by analyzing a panel of histone modifications in induced pluripotent stem cell-derived neural progenitors. CHD8 suppression led to significant reduction (47.82%) in histone H3K36me3 peaks at gene bodies, particularly impacting on transcriptional elongation chromatin states. H3K36me3 reduction specifically affects highly expressed, CHD8-bound genes and correlates with altered alternative splicing patterns of 408 genes implicated in “regulation of RNA splicing”, “mRNA catabolic process”. Interestingly, mass-spectrometry analysis uncovered a novel interaction between CHD8 and the splicing regulator Heterogeneous Nuclear Ribonucleoprotein L (hnRNPL), providing the first mechanistic insights to explain CHD8-suppression splicing phenotype, partially implicating SETD2, H3K36me3 methyltransferase. In summary, our results point toward broad molecular consequences of CHD8 suppression, entailing altered histone deposition/maintenance and RNA processing regulation as important regulatory processes in ASD.
2023-03-11 | PXD025739 | Pride
Project description:Haploinsufficiency of BCL6 impairs follicular T-B interactions
| PRJNA750642 | ENA
Project description:The packaging of DNA into chromatin determines the transcriptional potential of cells and is central to eukaryotic gene regulation. Case sequencing studies have revealed mutations to proteins that regulate chromatin state, known as chromatin remodeling factors, with causal roles in neurodevelopmental disorders. Chromodomain helicase DNA binding protein 8 (CHD8) encodes a chromatin remodeling factor with among the highest de novo loss-of-function mutation rates in patients with autism spectrum disorder (ASD). However, mechanisms associated with CHD8 pathology have yet to be elucidated. We analyzed published transcriptomic data across CHD8 in vitro and in vivo knockdown and knockout models and CHD8 binding across published ChIP-seq datasets to identify convergent mechanisms of gene regulation by CHD8. Differentially expressed genes (DEGs) across models varied, but overlap was observed between downregulated genes involved in neuronal development and function, cell cycle, chromatin dynamics, and RNA processing, and between upregulated genes involved in metabolism and immune response. Considering the variability in transcriptional changes and the cells and tissues represented across ChIP-seq analysis, we found a surprisingly consistent set of high-affinity CHD8 genomic interactions. CHD8 was enriched near promoters of genes involved in basic cell functions and gene regulation. Overlap between high-affinity CHD8 targets and DEGs shows that reduced dosage of CHD8 directly relates to decreased expression of cell cycle, chromatin organization, and RNA processing genes, but only in a subset of studies. This meta-analysis verifies CHD8 as a master regulator of gene expression and reveals a consistent set of high-affinity CHD8 targets across human, mouse, and rat in vivo and in vitro studies. These conserved regulatory targets include many genes that are also implicated in ASD. Our findings suggest a model where perturbation to dosage-sensitive CHD8 genomic interactions with a highly-conserved set of regulatory targets leads to model-specific downstream transcriptional impacts.
| S-EPMC6339895 | biostudies-literature