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Female cortical cellular mosaicism underlies shared MeCP2 and PCB impacted gene pathways

ABSTRACT: Etiologies of neurodevelopmental disorders involve genes and environment however their interactions are understudied. Rett Syndrome (RTT) is an X-linked, dominant neurodevelopmental disorder caused by mutations in MECP2, encoding the epigenetic regulator methyl CpG binding protein. The variability in severity and timing of progression in RTT, influenced by factors including mutation type, genetic background, and X-chromosome inactivation patterns, suggests potential interaction with environmental neurotoxicants such as lipophilic polychlorinated biphenyls (PCBs). Understanding these gene-by-environment interactions has broader implications for neurodevelopmental disorders, as MeCP2 dysregulation occurs in ~70% of autism spectrum disorder cases. To understand shared mechanisms, we exposed WT and Mecp2e1-/+ female mice to a human-relevant PCB mixture and dose, then performed single-nucleus 5’ RNA-seq from cortex. We identified significant overlap in dysregulated genes and 71 shared pathways between the effects of PCB exposure and MeCP2 mutation, and co-mitigation of their transcriptional impacts. PCBs influenced the non-cell-autonomous transcriptional effects of MeCP2 mutations in wild-type-expressing neurons within the mosaic mutant female cortex in both mouse and human, suggesting that the interactions predominantly involve homeostatic gene networks.

ORGANISM(S): Mus musculus

PROVIDER: GSE316011 | GEO | 2026/01/31

REPOSITORIES: GEO

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Project description:Background. Rett syndrome (RTT) is a complex neurodevelopmental disorder that is one of the most frequent causes of mental retardation in women. A great landmark in research in this field was the discovery of a relationship between the disease and the presence of mutations in the gene that codes for the methyl-CpG binding protein 2 (MeCP2). Currently, MeCP2 is thought to act as a transcriptional repressor that couples DNA methylation and transcriptional silencing. The present study aimed to identify new target genes directly regulated by Mecp2 in a mouse model of RTT. Methodology. We have compared the gene expression profiles of wild type (WT) and Mecp2-null (KO) mice in three regions of the brain (cortex, midbrain, and cerebellum) by using cDNA microarrays. The results obtained were confirmed by quantitative real-time PCR. Subsequent chromatin immunoprecipitation assays revealed seven direct target genes of Mecp2 bound in vivo (Dlk1, Mobp, Plagl1, Ddc, Mllt2h, Eya2, and S100a9), and two overexpressed genes due to an indirect effect of a lack of Mecp2 (Irak1 and Prodh). Bisulfite sequencing analysis of the methylation patterns of promoters of the described genes showed no differences between WT and KO mice, demonstrating that methylation differences were not the cause of the observed expression changes. Moreover, the regions bound by Mecp2 were always methylated, suggesting the involvement of the methyl-CpG binding domain of the protein in the mechanism of interaction. Conclusions. We identified new genes that are overexpressed in KO mice and are excellent candidate genes for involvement in various features of the neurodevelopmental disease. Our results demonstrate new targets of MeCP2 and provide us with a better understanding of the underlying mechanisms of RTT. Comparative experiment: Mecp2-null (KO) mice vs. their corresponding age-mated wild type (WT) littermates (CONTROLS). Four couples of KO-WT animals are used and three different brain regions are studied from each couple; cortex, midbrain, and cerebellum.

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Female cortical cellular mosaicism underlies shared MeCP2 and PCB impacted gene pathways

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