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Whole brain transcriptome analysis of heterozygous and homozygous Chd8 mutation (Asn2373LysfsX2) mice age of P0, P25 and P56 with C57BL6/J x 129/Sv background

ABSTRACT: Autism spectrum disorders (ASD) are 4–5 times more common in males, possibly due to female protective effects (FPEs), which suggests females are less susceptible to ASD unless a genetic mutation is particularly strong. If this is the case, increasing the strength of a ASD-risk mutation above the female threshold may induce ASD symptoms both in females and males. To this end, we compared male and female phenotypes in heterozygous and homozygous mice carrying a patient-derived CHD8 mutation (Asn2373LysfsX2), using a hybrid genetic background to overcome homozygous lethality. Heterozygous Chd8+/N2373K males and females displayed sexually dimorphic phenotypes stronger than those in homozygous Chd8 N2373 /N2373K males and females in behaviors, brain blood flow, neuronal activity, synaptic transmission, and transcriptomes. These results suggest that a stronger Chd8 mutation suppresses sexual dimorphism in mice, supporting the FPE hypothesis in ASD.

ORGANISM(S): Mus musculus

PROVIDER: GSE275918 | GEO | 2026/09/17

REPOSITORIES: GEO

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Cortex, hippocampus, striatum transcriptome analysis of Chd8 mutation (Asn2373LysfsX2) adult mice with C57BL/6J x 129/Sv background

Project description:Autism spectrum disorders (ASD) are 4–5 times more common in males, possibly due to female protective effects (FPEs), which suggests females are less susceptible to ASD unless a genetic mutation is particularly strong. If this is the case, increasing the strength of a ASD-risk mutation above the female threshold may induce ASD symptoms both in females and males. To this end, we compared male and female phenotypes in heterozygous and homozygous mice carrying a patient-derived CHD8 mutation (Asn2373LysfsX2), using a hybrid genetic background to overcome homozygous lethality. Heterozygous Chd8+/N2373K males and females displayed sexually dimorphic phenotypes stronger than those in homozygous Chd8 N2373 /N2373K males and females in behaviors, brain blood flow, neuronal activity, synaptic transmission, and transcriptomes. These results suggest that a stronger Chd8 mutation suppresses sexual dimorphism in mice, supporting the FPE hypothesis in ASD.

2026-09-17 | GSE275742 | GEO

Transcriptome analysis of Chd8 S62X heterozygote mutant and wild-type mice

Project description:Autism spectrum disorders (ASD) are ~4-times more common in males than females, and CHD8 (a chromatin remodeler)-related ASD shows a strong male bias (~5:1), although the underlying mechanism remains unclear. Chd8-mutant mice with a C-terminal protein-truncating mutation (N2373X) display male-preponderant behavioral deficits as juveniles and adults, although whether this also applies to other Chd8 mutations remains unknown. Here we report that new Chd8-mutant mice with a stronger N-terminal protein-truncating mutation (S62X) display male-preponderant autistic-like behaviors at juvenile stages, but as adults, both males and females share behavioral deficits. Excitatory synaptic transmission is suppressed and enhanced in male and female juvenile Chd8+/S62X mice, respectively, but similarly enhanced in adults. ASD-like transcriptomic changes occur monophasically in newborn and juvenile (but not adult) males but biphasically in newborn and adult (not juvenile) females. Therefore, a strong CHD8 mutation induces early-onset ASD-like phenotypes in males but late-onset phenotypes in females after juvenile-stage female protection.

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Cortex transcriptome analysis of CHD8 Asn2373LysfsX2 heterozygote mutation mice age of P25

Project description:CHD8, encoding a chromatin remodeling protein, is one of the most frequently mutated genes in autism spectrum disorders. However, how such mutations cause autistic behaviors remain unclear. In mice carrying a heterozygous frame-shift mutation in the Chd8 gene (Asn2373LysfsX2) identified in autistic human individuals, we observed autistic-like behaviors that are much stronger in males than in females, similar to human cases. These behaviors included enhanced mother-seeking ultrasonic vocalizations in pups, mother-attachment behaviors in juveniles, and isolation-induced self-grooming in adults. These behaviors were associated with opposite changes in synaptic excitation/inhibition and neuronal firing in male and female mice, but with strong changes in gene expression in female mice. Therefore, this CHD8 mutation may cause male-preponderant autistic-like behaviors in mice through differential synaptic/neuronal changes and gene expression

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Comparison of DEG between neonatal male and female mice age of P25 by CHD8 Asn2373LysfsX2 heterozygote mutation.

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CHD8 dosage regulates transcription in pluripotency and early murine neural differentiation [RNA-seq]

Project description:The chromatin remodeler CHD8 is among the most frequently mutated genes in autism spectrum disorder (ASD). CHD8 has a dosage-sensitive role in ASD but when and how it becomes critical to human social function is unclear. Here, we conducted genomic analyses of heterozygous and homozygous Chd8 mouse embryonic stem cells and differentiated neural progenitors. We identify dosage-sensitive CHD8 transcriptional targets, sites of regulated accessibility, and an unexpected cooperation with SOX transcription factors. Collectively, our findings reveal that CHD8 negatively regulates expression of neuronal genes to maintain pluripotency and also during differentiation. Thus, CHD8 is essential for both the maintenance of pluripotency and neural differentiation, providing mechanistic insight into its function with potential implications for ASD.

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CHD8 dosage regulates transcription in pluripotency and early murine neural differentiation [ChIP-seq]

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CHD8 dosage regulates transcription in pluripotency and early murine neural differentiation [ATAC-seq]

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Comparison of DEG between neonatal male and female mice age of P0 by CHD8 Asn2373LysfsX2 heterozygote mutation

Project description:CHD8, encoding a chromatin remodeling protein, is one of the most frequently mutated genes in autism spectrum disorders (ASDs) 1-8. However, whether and how such mutations cause autistic behaviors remain unclear. Here we show that a human CHD8 mutation causes autistic-like behaviors and enhanced excitatory drive specifically in male mice. We found that knockin mice carrying a heterozygous frame-shift mutation in the Chd8 gene (Asn2373LysfsX2) identified in human individuals with ASDs (Chd8+/N2373K mice) display male-specific autistic-like behaviors. Gene transcript analysis shows that male and female Chd8+/N2373K neurons exhibit largely opposite changes in the levels of 29 mRNAs, nine of which correspond to known ASD-risk genes. These results suggest that a human CHD8 mutation causes male-specific autistic-like behaviors in mice in association with gender-specific differential changes in gene transcripts and excitatory drive in the brain.

2018-06-15 | GSE80803 | GEO

Transcriptomic Convergence and the Female Protective Effect in Autism [RNA-Seq, NPC_shRNA_KD]

Project description:Autism spectrum disorder (ASD) is a common neurodevelopmental condition characterized by deficits in social communication as well as restricted and/or repetitive behaviors. ASD is highly heritable, with a complex genetic architecture: large-scale studies have identified dosage-altering copy number variants (CNV) and single nucleotide variants (SNV) that implicate hundreds of genes as individually rare causes of ASD (ASD genes), with common variation at multiple loci also contributing substantially to risk. Understanding how disruptions to these functionally diverse genes lead to the shared core features of ASD remains a major challenge. Moreover, ASD is three- to four-fold more common in males than females, and autistic females tend to carry more autosomal risk alleles for ASD compared to autistic males, but the biological basis of this “female protective effect” (FPE) is unknown. Here we show that individual perturbations of 18 ASD genes in human neural progenitor cells converge on shared effects on gene expression, including widespread downregulation of other ASD genes. De novo reconstruction of a gene regulatory network (GRN) enabled the identification of central transcriptional regulators, including the prominent ASD gene CHD8 as well as novel candidates such as REST, that drive this transcriptomic convergence. Furthermore, the X-linked transcription factor ZFX, which is expressed from both the active and the inactive X chromosomes in females, emerged as a key activator of many ASD genes: we propose that the higher ZFX expression level observed in female brain can buffer damaging mutations in diverse ASD genes, contributing to the FPE. Together, these results reveal how key GRNs can become broadly and similarly dysregulated upon disruption of individual ASD genes and provide molecular insight into the female protective effect in ASD.

2026-09-16 | GSE332571 | GEO

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