Cell type-specific gene expression patterns associated with posttraumatic stress disorder in World Trade Center responders

Abstract

Posttraumatic stress disorder (PTSD), a chronic disorder resulting from severe trauma, has been linked to immunologic dysregulation. Gene expression profiling has emerged as a promising tool for understanding the pathophysiology of PTSD. However, to date, all but one gene expression study was based on whole blood or unsorted peripheral blood mononuclear cell (PBMC), a complex tissue consisting of several populations of cells. The objective of this study was to utilize RNA sequencing to simultaneously profile the gene expression of four immune cell subpopulations (CD4T, CD8T, B cells, and monocytes) in 39 World Trade Center responders (20 with and 19 without PTSD) to determine which immune subsets play a role in the transcriptomic changes found in whole blood. Transcriptome-wide analyses identified cell-specific and shared differentially expressed genes across the four cell types. FKBP5 and PI4KAP1 genes were consistently upregulated across all cell types. Notably, REST and SEPT4, genes linked to neurodegeneration, were among the top differentially expressed genes in monocytes. Pathway analyses identified differentially expressed gene sets involved in mast cell activation and regulation in CD4T, interferon-beta production in CD8T, and neutrophil-related gene sets in monocytes. These findings suggest that gene expression indicative of immune dysregulation is common across several immune cell populations in PTSD. Furthermore, given notable differences between cell subpopulations in gene expression associated with PTSD, the results also indicate that it may be valuable to analyze different cell populations separately. Monocytes may constitute a key cell type to target in research on gene expression profile of PTSD.

Exposure to the predator odor TMT induces early and late differential gene expression related to stress and excitatory synaptic function throughout the brain in male rats

“…Binding of cortisol to the GR downregulates corticotropin releasing factor (CRF) expression in the hypothalamus, acting as a negative feedback of HPA‐axis activation 13 . Interestingly, in PTSD participants, the FK506 binding protein 5 (FKBP5), a chaperone protein that affects GR and mineralocorticoid receptor (MR) binding sensitivity for glucocorticoids and inhibits cellular translocation, is differentially expressed in several RNA sequencing studies compared with control participants both in peripheral blood cells, and postmortem PFC brain tissue 14‐16 . Together, these data provide strong support for the hypothesis that PTSD is associated with a persistent dysregulation in the canonical HPA‐axis stress system 4 …”

Exposure to the predator odor TMT induces early and late differential gene expression related to stress and excitatory synaptic function throughout the brain in male rats

“…Binding of cortisol to the GR downregulates corticotropin releasing factor (CRF) expression in the hypothalamus, acting as a negative feedback of HPA-axis activation 13 . Interestingly, in PTSD participants, the FK506 binding protein 5 (FKBP5), a chaperone protein that affects GR and mineralocorticoid receptor (MR) binding sensitivity for glucocorticoids and inhibits cellular translocation, is differentially expressed in several RNA sequencing studies compared to control participants both in peripheral blood cells, and post-mortem PFC brain tissue 14,15,16 . Together, these data provide strong support for the hypothesis that PTSD is associated with a persistent dysregulation in the canonical HPA-axis stress system 4 .…”

<p>Resilience In Dogs? Lessons From Other Species</p>

“…These loci are not, however, the only genetic factors affecting anxiety and aggression in dogs. A recent study found a genomic area in German Shepherds, that differed between dogs having noise fear and those without noise fear 79. The same study identified genetic differences (from another chromosome) between fearful and non-fearful dogs 79.…”

“…A recent study found a genomic area in German Shepherds, that differed between dogs having noise fear and those without noise fear 79. The same study identified genetic differences (from another chromosome) between fearful and non-fearful dogs 79. In addition, a study focusing on breed differences in behavioral traits observed very high heritabilities (h 2 : 0.27–0.77) for 14 behavioral traits such as aggression and fear towards strangers, trainability, and non-social social fear, and moreover, found 131 single nucleotide polymorphism associated with behavior 80.…”