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Study Suggests Epigenetic Regulation of Pro-Inflammatory Cytokines in PTSD

NEW YORK (GenomeWeb) – Some cells from patients diagnosed with post-traumatic stress disorder (PTSD) show evidence of epigenetic regulation of the pro-inflammatory cytokines interleukin-12 (IL-12) and interferon gamma (IFNG), according to a new study.

Scientists led by co-first authors Marpe Bam and Xaioming Yang and senior author Mitzi Nagarkatti of the University of South Carolina studied genome-wide histone and DNA methylation in peripheral blood mononuclear cells (PBMCs) from PTSD patients. They found "significant differences" in histone H3 trimethylation at several sites as well as differential methylation of promoters of genes related to inflammation.

The authors said that PTSD patients showed higher transcript levels of IFNG and increased expression of IL-12, which could have been activated by epigenetic modification. A microarray study of microRNAs (miRNA) found downregulation of several miRNAs predicted to target IFNG and IL-12. The biomarkers could be used to diagnose and treat PTSD, the authors implied.

They published their results Nov. 20 in the Journal of Neuroimmune Pharmacology.

The study builds off previous work from Nagarkatti's lab on epigenetic regulation of the immune response in PTSD. In a 2014 study published in PLoS One, Nagarkatti led a team that showed elevated PBMC counts in patients with PTSD as well as cytokine dysregulation and differential miRNA expression in those patients. In particular, they found that IFNG was significantly increased in PBMCs.

Inflammation is of particular interest to PTSD-related research because patients with PTSD have a higher incidence of other conditions associated with inflammation such as metabolic, neurologic, and autoimmune disorders. "Increasing evidence indicates that immune function is one of the dysregulated functions in PTSD patients," the authors wrote, adding that their and others' previous work had shown cytokine abnormalities in blood samples from PTSD patients.

Using ChIP-seq, the scientists showed differential histone methylation at H3K4me3, H3K27me3, H3K36me3, and H3K9me3. However, they did not detect significant differences in DNA methylation between PTSD patients and controls.

Looking specifically to explain the rise in IFNG in PBMCs for PTSD patients, they examined gene expression. The ChIP-seq data "revealed that the IFNG gene in PTSD was associated with the activation marker H3K4me3 while this marker was absent in the control.

Using microarrays, the researchers also found numerous miRNAs that were downregulated in the PTSD samples. "Many of the downregulated miRNAs are predicted to directly target IL-12," the authors wrote, "suggesting that the expression of the pro-inflammatory cytokine will be further increased."

The results could be used to inform diagnosis as well as lead to new strategies to not only treat PTSD but also PTSD-related clinical disorders, the authors said.