Skip to main content
[Preprint]. 2024 Jul 9:2024.07.09.602755. [Version 1] doi: 10.1101/2024.07.09.602755

Figure 1. Stress and inflammatory factors impacted gene expression, chromatin accessibility, cell morphology, but not survival, in developing neurons.

Figure 1.

Differential gene expression analysis in iGLUTs exposed to 1000nM hCort, 60ng/uL IL-6, or 500 UI/mL IFNa-2b (compared to vehicle) revealed unique and shared effects on the transcriptome. (A) 1000nM hCort resulted in transcriptomic-wide dysregulation, while the effects of 60ng/mL IL-6 produced moderate downregulation of few genes, and IFNa-2b resulted in strong upregulation of select immune-related genes. (B) Overlapping (i) significant (FDR<0.05) and (ii) nominally significant (unadjusted p-value<0.05) DEGs by cue. (C) Signed pathway enrichment of cue-specific transcriptomic dysregulation (DEGs; unadjusted p-value<0.05) (Supplemental Data 2). (D-F) Gene expression changes in the mouse amygdala, frontal cortex, and whole brain following Poly(I∣C), IL6, or H1N1-induced MIA significantly correlated with transcriptomic signatures of IL-6 and hCort. (i) Heatmap of log2FC across shared genes. (ii) Pearson’s correlation of log2FC across cue-exposures and MIA-induced mouse brain DEGs (# = FDR<0.08; * = FDR<0.05; ** = FDR<0.01; *** = FDR<0.001). (iii) Overlap of nominal significantly different DEGs and MIA-induced mouse brain DEGs (G) Enrichment of cue-specific dysregulation (DEGs; unadjusted p-value<0.05) for MIA-induced fetal brain DEGs across MIA rodent models. (H) Enrichment of cue-specific transcriptomic dysregulation (DEGs; unadjusted p-value<0.05) for GWAS risk genes across psychiatric, neurological, and immune traits. # = FDR<0.08; * = FDR<0.05; ** = FDR<0.01; *** = FDR<0.001. (I) Differential peak accessibility analysis in iGLUTs exposed to 1000nM hCort, 60ng/uL IL-6, or 500 UI/mL IFNa-2b (compared to vehicle) showed significant decreases in chromatin accessibility following exposure to IL-6. (J) Dose-dependent impact of exposure of hCort, IL-6, and IFNa-2b on early (D7) neurite outgrowth in iGLUTs. (i-iii) Exposure of 1000nM and 2500nM hCort significantly decreased early neurite outgrowth while exposure to (K) (i-iii) 100 UI/mL and 500 UI/mL IFNa-2b increased neurite outgrowth, relative to vehicle control conditions. N = minimum of 2 independent experiments across 2 donor lines with 12 technical replicates per condition and 9 images analyzed per replicate. One way ANOVA with post-hoc Bonferroni multiple comparisons test. * = p<0.05; ** = p<0.01; *** = p<0.001; **** = p<0.0001.