Microglia from offspring of dams with allergic asthma exhibit epigenomic alterations in genes dysregulated in autism

Abstract

Dysregulation in immune responses during pregnancy increase the risk of a having a child with an autism spectrum disorder (ASD). Asthma is one of the most common chronic diseases among pregnant women, and symptoms often worsen during pregnancy. We recently developed a mouse model of maternal allergic asthma (MAA) that induces changes in sociability, repetitive and perseverative behaviors in the offspring. Since epigenetic changes help a static genome adapt to the maternal environment, activation of the immune system may epigenetically alter fetal microglia, the brains resident immune cells. We therefore tested the hypothesis that epigenomic alterations to microglia may be involved in behavioral abnormalities observed in MAA offspring. We used the genome-wide approaches of whole genome bisulfite sequencing to examine DNA methylation and RNA sequencing to examine gene expression in microglia from juvenile MAA offspring. Differentially methylated regions (DMRs) were enriched for immune signaling pathways and important microglial developmental transcription factor binding motifs. Differential expression analysis identified genes involved in controlling microglial sensitivity to the environment and shaping neuronal connections in the developing brain. Differentially expressed associated genes significantly overlapped genes with altered expression in human ASD cortex, supporting a role for microglia in the pathogenesis of ASD.\n\nMain PointsMaternal allergic asthma induces changes in DNA methylation and transcription in juvenile offspring microglia\n\nDifferentially methylated regions are enriched for functions and transcription factor binding motifs involved in inflammation and microglial development\n\nDifferentially expressed genes and differentially methylated regions are enriched for genes dysregulated in Autism Spectrum Disorders