21606
Maternal Immune Activation Dysregulation of the Fetal Brain Transcriptome and Relevance to the Pathophysiology of Autism
Objectives: We tested the hypothesis that MIA-induced gene expression dysregulation would hit ASD-associated genes. These genes have been prioritized based on highly penetrant and recurrent “likely gene-disrupting” variants as well as missense mutations found in large genomic ASD studies. We also aimed to identify the transcriptional changes, both at the single gene level and at the network level, characteristic of the ASD postmortem brain that are shared in the MIA rat fetal brain.
Methods: We employed differential expression (DE) analyses to identify genes and networks dysregulation in ASD and MIA cortical transcriptomes. We used two publicly available datasets, Voineagu and colleagues (2011; GEO: GSE28521) and Oskvig and colleagues (2012; GEO: GSE34058). DE analyses were performed using the sva and limma packages. Network analyses were performed using the WGCNA package. Functional enrichment analyses were performed using the MetaCore GeneGO software.
Results: We show that MIA-dysregulated midgestational fetal brain gene expression is substantially enriched in highly penetrant ASD-associated genetic mechanisms. MIA downregulates pathways involved in synaptic processes, but upregulates translation initiation processes and both sets of processes are similarly dysregulated in the postnatal ASD cortical transcriptome. Upregulated translation initiation co-expression modules are highly preserved across MIA and ASD. The cap-dependent translation initiation gene EIF4E is the most affected ASD-associated gene (Cohen’s d = 8.27) and targeted analyses demonstrate prominent MIA-dysregulation of EIF4E-dependent networks and mechanisms.
Conclusions: This work identifies several routes through which MIA can dysregulate fetal brain gene expression that are highly relevant to ASD.