Chd8 haploinsufficiency impairs early brain development and impacts protein homeostasis later in life
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ABSTRACT:
PROVIDER: PRJNA596222 | ENA |
REPOSITORIES: ENA
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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: Not available
| 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: Not available
| S-EPMC6339895 | biostudies-literature