Every good gardener appreciates that pruning represents an essential part of encouraging healthy development. This principle holds true not only on the macroscopic level but also at the microscopic level of our brain’s synaptic connections, which rely on pruning by its resident immune cells: microglia. In order to sculpt neurodevelopment, microglia rely on environmental signals, which has spurred the labs of Paul Ashwood and Janine LaSalle at the University of California, Davis, to investigate how they fit into the interplay of environment and DNA methylation in autism spectrum disorders (ASD).
First author Annie Vogel Ciernia shares, “We wanted to identify some of the mechanisms underlying the epidemiology findings that maternal allergic asthma increases the risk of having a child with ASD. You have this maternal allergic asthma event during pregnancy, and then you have these very long-lasting effects on the offspring’s behavior. We wanted to figure out what mechanisms might underlie some of these long-term effects. We looked at immune cells in brain, which were prime suspects for contributing to the long-term changes in the offspring.”
To accomplish this, the team utilized a mouse model of maternal allergic asthma and examined microglia in juvenile offspring. Here’s what transpired when they analyzed DNA methylation and gene expression via whole-genome bisulfite sequencing (WGBS) and RNA-seq:
- A comparison of the DNA methylation and gene expression signatures with other cell-type specific data sets via principal component analysis (PCA) confirmed the purity of their microglia
- The differentially methylated regions (DMRs) are primarily intronic and intergenic, enriched for in transcription factor binding sites related to early microglia development, and regulate genes involved in immune signaling pathways
- The differentially expressed genes (DEGs) are related to neurodevelopment, specifically the shaping of neuronal connections, as well as the response of microglia to environmental signals
- Notably, there is very little overlap between DMRs and DEGs, although the genes that do overlap are related to neurodevelopment and autism risk
Finally, as Vogel Ciernia summarizes, “The genes we identified that had differences in methylation and changes in expression showed an enrichment for genes that had been identified as genetic risk factors for autism, as well as genes that were differentially expressed in autism human brain samples.” Co-senior author Janine LaSalle adds, “This is an environmental model, but we’re coming back to the same genes that can be genetically mutated and cause autism in rare cases. That overlap with some of the genes was pretty striking.”
Overall, the findings leave Vogel Ciernia with the outlook that “The ultimate goal would be to identify the pathways that are impacted, which could be a therapeutic target to reverse changes and potentially improve behaviors. But we need to have a better handle on whether these changes are driving the condition or compensation to a disruption in brain development.”
Go see why these findings are nothing to sneeze at in Glia, November 2017.