title: Evidence for Epigenetic Regulation of Pro-Inflammatory Cytokines, Interleukin-12 and Interferon Gamma, in Peripheral Blood Mononuclear Cells from PTSD Patients.
abstract: While Post Traumatic Stress Disorder (PTSD) is associated with immune dysfunction, the underlying mechanisms remain unclear. Studies suggest a role for involvement of epigenetic mechanisms and microRNAs (miRNAs). Here, we examined genome-wide histone and DNA methylation in the peripheral blood mononuclear cells (PBMCs) in PTSD. We noted significant differences in histone H3 trimethylation at K4, K9, K27 and K36 sites in PTSD when compared to control. While overall DNA methylation level did not differ significantly between control and PTSD, the promoters of several individual genes (e.g., Interferon gamma (IFNG) and Interleukin (IL)-12B) were differentially methylated. ChIP-seq data revealed that the promoter of IFNG and TBX-21 was associated with the activation marker H3K4me3 in PTSD. The transcript levels of both IFNG and TBX-21 were higher in PTSD correlating well with the altered methylation patterns. Furthermore, PTSD patients showed increased expression of IL-12 in their PBMCs. Analysis of both histone and DNA methylation markers suggested that the expression of IL-12 was also possibly activated through epigenetic modification. Knockdown of lysine (K)-specific demethylase 5B (KDM5B), or inhibition of DNA (Cytosine-5-)-methyltransferase 1 (DNMT1) caused up-regulation of IL-12. Furthermore, the expression of these cytokines was also regulated by miRNAs. Our miRNA microarray identified many downregulated miRNAs in PTSD that are predicted to target IFNG and IL-12. Consequently, we showed that up-regulation of hsa-miR-193a-5p could decrease the expression of IL-12. Overall, the current study demonstrated that the elevated expression of pro-inflammatory cytokines in PTSD patients might be regulated by multiple epigenetic mechanisms and miRNAs.
authors.affiliation: Department of Pathology, Microbiology and Immunology, School of Medicine, University of South Carolina, Columbia, SC 29209, USA.
authors.forename: Marpe
authors.initials: M
authors.lastname: Bam
authors.affiliation: Department of Pathology, Microbiology and Immunology, School of Medicine, University of South Carolina, Columbia, SC 29209, USA.
authors.forename: Xiaoming
authors.initials: X
authors.lastname: Yang
authors.affiliation: Department of Pathology, Microbiology and Immunology, School of Medicine, University of South Carolina, Columbia, SC 29209, USA.
authors.forename: Juhua
authors.initials: J
authors.lastname: Zhou
authors.affiliation: William Jennings Bryan Dorn Veterans Medical Center, 6439 Garners Ferry Road, Columbia, South Carolina 29209-1639.
authors.forename: Jay P
authors.initials: JP
authors.lastname: Ginsberg
authors.affiliation: William Jennings Bryan Dorn Veterans Medical Center, 6439 Garners Ferry Road, Columbia, South Carolina 29209-1639.
authors.forename: Quinne
authors.initials: Q
authors.lastname: Leyden
authors.affiliation: Department of Pathology, Microbiology and Immunology, School of Medicine, University of South Carolina, Columbia, SC 29209, USA.
authors.forename: Prakash S
authors.initials: PS
authors.lastname: Nagarkatti
authors.affiliation: Department of Pathology, Microbiology and Immunology, School of Medicine, University of South Carolina, Columbia, SC 29209, USA.|William Jennings Bryan Dorn Veterans Medical Center, 6439 Garners Ferry Road, Columbia, South Carolina 29209-1639.
authors.forename: Mitzi
authors.initials: M
authors.lastname: Nagarkatti
mesh_terms: D000111:Acetylcysteine; D000328:Adult; D047369:Chromatin Immunoprecipitation; D016207:Cytokines / Q000096:biosynthesis*; D019175:DNA Methylation / Q000276:immunology; D044127:Epigenesis, Genetic; D005260:Female; D005786:Gene Expression Regulation; D055785:Gene Knockdown Techniques; D006801:Humans; D007371:Interferon-gamma / Q000096:biosynthesis*; D018664:Interleukin-12 / Q000096:biosynthesis*; D007963:Leukocytes, Mononuclear / Q000276:immunology* / Q000378:metabolism; D008297:Male; D011401:Promoter Regions, Genetic / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D013313:Stress Disorders, Post-Traumatic / Q000235:genetics / Q000276:immunology*; D014162:Transfection
chemical_list: D016207:Cytokines; D018664:Interleukin-12; D007371:Interferon-gamma; D000111:Acetylcysteine
keywords: DNA methylation; Histone modification; IL-12; Inflammation; Post-traumatic stress disorder; miRNA