Quinne Leyden

Bio: Quinne Leyden is an academic researcher from William Jennings Bryan Dorn VA Medical Center. The author has contributed to research in topics: Regulation of gene expression & DNA methylation. The author has an hindex of 3, co-authored 3 publications receiving 111 citations.

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.

Dysregulated immune system networks in war veterans with PTSD is an outcome of altered miRNA expression and DNA methylation.

Abstract: Post-traumatic stress disorder patients experience chronic systemic inflammation. However, the molecular pathways involved and mechanisms regulating the expression of genes involved in inflammatory pathways in PTSD are reported inadequately. Through RNA sequencing and miRNA microarray, we identified 326 genes and 190 miRNAs that were significantly different in their expression levels in the PBMCs of PTSD patients. Expression pairing of the differentially expressed genes and miRNAs indicated an inverse relationship in their expression. Functional analysis of the differentially expressed genes indicated their involvement in the canonical pathways specific to immune system biology. DNA methylation analysis of differentially expressed genes also showed a gradual trend towards differences between control and PTSD patients, again indicating a possible role of this epigenetic mechanism in PTSD inflammation. Overall, combining data from the three techniques provided a holistic view of several pathways in which the differentially expressed genes were impacted through epigenetic mechanisms, in PTSD. Thus, analysis combining data from RNA-Seq, miRNA array and DNA methylation, can provide key evidence about dysregulated pathways and the controlling mechanism in PTSD. Most importantly, the present study provides further evidence that inflammation in PTSD could be epigenetically regulated.

Decreased AGO2 and DCR1 in PBMCs from War Veterans with PTSD leads to diminished miRNA resulting in elevated inflammation.

Abstract: Chronic inflammation is a characteristic of post-traumatic stress disorder (PTSD). The initiation of inflammation and molecules involved are not yet clearly understood. Here, we provide compelling evidence that the inflammation seen in PTSD may result from the dysregulated miRNA processing pathway. Using microarray analysis with a discovery group of peripheral blood mononuclear cell (PBMC) samples from War Veterans with PTSD, we found 183 significantly downregulated miRNAs, several of which target numerous genes categorized to be pro-inflammatory in nature. This observation was further confirmed in a replicate group by including more samples. Furthermore, employing RNA-sequencing, quantitative real time PCR (qRT-PCR) and in vitro experiments, we found that Argonaute 2 (AGO2) and Dicer1 (DCR1) were downregulated in PTSD and provided convincing evidence that their downregulation affects mature miRNA generation. In addition, we noted that STAT3 transcript was reduced in PTSD and this was possibly responsible for reduced AGO2 and DCR1, which in turn affected miRNA synthesis. Furthermore, we observed that activation of CD4+ T cells or monocytes led to reduced mature miRNA availability. Finally, the inflammation seen in PTSD was associated with downregulated miRNA profile. Altogether, the current study demonstrates that the chronic inflammation seen in PTSD may be a result of dysregulated miRNA biogenesis pathway due to diminished expression of the key molecules like AGO2, DCR1 and STAT3.

Developmental Trajectories of Early Life Stress and Trauma: A Narrative Review on Neurobiological Aspects Beyond Stress System Dysregulation

Abstract: Early life stressors display a high universal prevalence and constitute a major public health problem. Prolonged psychoneurobiological alterations as sequelae of early life stress (ELS) could represent a developmental risk factor and mediate risk for disease, leading to higher physical and mental morbidity rates in later life. ELS could exert a programming effect on sensitive neuronal brain networks related to the stress response during critical periods of development and thus lead to enduring hyper- or hypo-activation of the stress system and altered glucocorticoid signaling. In addition, alterations in emotional and autonomic reactivity, circadian rhythm disruption, functional and structural changes in the brain, as well as immune and metabolic dysregulation have been lately identified as important risk factors for a chronically impaired homeostatic balance after ELS. Furthermore, human genetic background and epigenetic modifications through stress-related gene expression could interact with these alterations and explain inter-individual variation in vulnerability or resilience to stress. This narrative review presents relevant evidence from mainly human research on the ten most acknowledged neurobiological allostatic pathways exerting enduring adverse effects of ELS even decades later (hypothalamic-pituitary-adrenal axis, autonomic nervous system, immune system and inflammation, oxidative stress, cardiovascular system, gut microbiome, sleep and circadian system, genetics, epigenetics, structural, and functional brain correlates). Although most findings back a causal relation between ELS and psychobiological maladjustment in later life, the precise developmental trajectories and their temporal coincidence has not been elucidated as yet. Future studies should prospectively investigate putative mediators and their temporal sequence, while considering the potentially delayed time-frame for their phenotypical expression. Better screening strategies for ELS are needed for a better individual prevention and treatment.

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.

Molecular pathological epidemiology: new developing frontiers of big data science to study etiologies and pathogenesis

Abstract: Molecular pathological epidemiology (MPE) is an integrative field that utilizes molecular pathology to incorporate interpersonal heterogeneity of a disease process into epidemiology. In each individual, the development and progression of a disease are determined by a unique combination of exogenous and endogenous factors, resulting in different molecular and pathological subtypes of the disease. Based on "the unique disease principle," the primary aim of MPE is to uncover an interactive relationship between a specific environmental exposure and disease subtypes in determining disease incidence and mortality. This MPE approach can provide etiologic and pathogenic insights, potentially contributing to precision medicine for personalized prevention and treatment. Although breast, prostate, lung, and colorectal cancers have been among the most commonly studied diseases, the MPE approach can be used to study any disease. In addition to molecular features, host immune status and microbiome profile likely affect a disease process, and thus serve as informative biomarkers. As such, further integration of several disciplines into MPE has been achieved (e.g., pharmaco-MPE, immuno-MPE, and microbial MPE), to provide novel insights into underlying etiologic mechanisms. With the advent of high-throughput sequencing technologies, available genomic and epigenomic data have expanded dramatically. The MPE approach can also provide a specific risk estimate for each disease subgroup, thereby enhancing the impact of genome-wide association studies on public health. In this article, we present recent progress of MPE, and discuss the importance of accounting for the disease heterogeneity in the era of big-data health science and precision medicine.

Dysregulated immune system networks in war veterans with PTSD is an outcome of altered miRNA expression and DNA methylation.

Abstract: Post-traumatic stress disorder patients experience chronic systemic inflammation. However, the molecular pathways involved and mechanisms regulating the expression of genes involved in inflammatory pathways in PTSD are reported inadequately. Through RNA sequencing and miRNA microarray, we identified 326 genes and 190 miRNAs that were significantly different in their expression levels in the PBMCs of PTSD patients. Expression pairing of the differentially expressed genes and miRNAs indicated an inverse relationship in their expression. Functional analysis of the differentially expressed genes indicated their involvement in the canonical pathways specific to immune system biology. DNA methylation analysis of differentially expressed genes also showed a gradual trend towards differences between control and PTSD patients, again indicating a possible role of this epigenetic mechanism in PTSD inflammation. Overall, combining data from the three techniques provided a holistic view of several pathways in which the differentially expressed genes were impacted through epigenetic mechanisms, in PTSD. Thus, analysis combining data from RNA-Seq, miRNA array and DNA methylation, can provide key evidence about dysregulated pathways and the controlling mechanism in PTSD. Most importantly, the present study provides further evidence that inflammation in PTSD could be epigenetically regulated.