Dataset Information

Chd8 haploinsufficiency impairs early brain development and protein homeostasis later in life.

ABSTRACT:

Background

Chromodomain 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.

Methods

We 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).

Results

Chd8^V986*/+ 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 Chd8^V986*/+ mutant mice at 1 year of age. Pup survival was reduced in wild-type x Chd8^V986*/+ 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 Chd8^V986*/+ 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 Chd8^V986*/+ mice, whereas genes associated with the c-MET signaling pathway were increased in expression.

Limitations

It is unclear whether the transcriptional changes observed with age in Chd8^V986*/+ 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.

Conclusions

Collectively, these data suggest that UPR/ER stress pathways are reduced in the cerebral cortex of aged Chd8^V986*/+ mice. Our study uncovers neurodevelopmental and age-related phenotypes in Chd8^V986*/+ mice and highlights the importance of controlling for age when studying Chd8 haploinsufficient mice.

SUBMITTER: Jimenez JA

PROVIDER: S-EPMC7537101 | biostudies-literature |

REPOSITORIES: biostudies-literature

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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.