Evidence for Epigenetic Regulation of Pro-Inflammatory Cytokines, Interleukin-12 and Interferon Gamma, in Peripheral Blood Mononuclear Cells from PTSD Patients View Full Text


Ontology type: schema:ScholarlyArticle      Open Access: True


Article Info

DATE

2015-11-20

AUTHORS

Marpe Bam, Xiaoming Yang, Juhua Zhou, Jay P. Ginsberg, Quinne Leyden, Prakash S. Nagarkatti, Mitzi Nagarkatti

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. More... »

PAGES

168-181

References to SciGraph publications

Identifiers

URI

http://scigraph.springernature.com/pub.10.1007/s11481-015-9643-8

DOI

http://dx.doi.org/10.1007/s11481-015-9643-8

DIMENSIONS

https://app.dimensions.ai/details/publication/pub.1036324869

PUBMED

https://www.ncbi.nlm.nih.gov/pubmed/26589234


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40 schema:description 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.
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48 DNA
49 DNA methylation
50 DNA methylation levels
51 DNA methylation markers
52 H3 trimethylation
53 H3K4me3
54 IFNG
55 IL-12
56 K27
57 K36 sites
58 K4
59 K9
60 Knockdown of lysine
61 PTSD patients
62 TBX-21
63 Traumatic Stress Disorder
64 activation marker H3K4me3
65 analysis
66 blood mononuclear cells
67 cells
68 control
69 current study
70 cytokines
71 cytosine-5
72 data
73 demethylase 5B
74 differences
75 disorders
76 dysfunction
77 elevated expression
78 epigenetic mechanisms
79 epigenetic modifications
80 epigenetic regulation
81 evidence
82 expression
83 gamma
84 genes
85 genome-wide histone
86 histone H3 trimethylation
87 histones
88 immune dysfunction
89 individual genes
90 inflammatory cytokines
91 inhibition
92 inhibition of DNA
93 interferon gamma
94 interleukin-12
95 involvement
96 knockdown
97 levels
98 lysine
99 markers
100 mechanism
101 methylation
102 methylation levels
103 methylation markers
104 methylation patterns
105 methyltransferase 1
106 miRNA microarray
107 miRNAs
108 microRNAs
109 microarrays
110 modification
111 mononuclear cells
112 multiple epigenetic mechanisms
113 overall DNA methylation level
114 patients
115 patterns
116 peripheral blood mononuclear cells
117 post-traumatic stress disorder
118 pro-inflammatory cytokines
119 promoter
120 promoter of IFNG
121 regulation
122 role
123 significant differences
124 sites
125 specific demethylase 5B
126 stress disorder
127 study
128 transcript levels
129 trimethylation
130 schema:name Evidence for Epigenetic Regulation of Pro-Inflammatory Cytokines, Interleukin-12 and Interferon Gamma, in Peripheral Blood Mononuclear Cells from PTSD Patients
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