Project description:The molecular factors involved in the development of Post-traumatic Stress Disorder (PTSD) remain poorly understood. Previous transcriptomic studies investigating the mechanisms of PTSD apply targeted approaches to identify individual genes under a cross-sectional framework lack a holistic view of the behaviours and properties of these genes at the system-level. Here we sought to apply an unsupervised gene-network-based approach to a prospective experimental design using whole-transcriptome RNA-Seq gene expression from peripheral blood leukocytes of U.S. Marines (N=188), obtained both pre- and post-deployment to conflict zones. We identified discrete groups of co-regulated genes (i.e., co-expression modules) and tested them for association to PTSD. We identified one module at both pre- and post-deployment containing putative causal signatures for PTSD development displaying an over-expression of genes enriched for functions of innate-immune response and interferon signalling (Type-I and Type-II). Importantly, these results were replicated in a second non-overlapping independent dataset of U.S. Marines (N=96), further outlining the role of innate immune and interferon signalling genes within co-expression modules to explain at least part of the causal pathophysiology for PTSD development. A second module, consequential of trauma exposure, contained PTSD resiliency signatures and an over-expression of genes involved in hemostasis and wound responsiveness suggesting that chronic levels of stress impair proper wound healing during/after exposure to the battlefield while highlighting the role of the hemostatic system as a clinical indicator of chronic-based stress. These findings provide novel insights for early preventative measures and advanced PTSD detection, which may lead to interventions that delay or perhaps abrogate the development of PTSD. We used microarrays to characterize both prognostic and diagnostic molecular signatures associated to PTSD risk and PTSD status compared to control subjects. Peripheral blood leukocytes gene expression was subject to transcriptional analysis for 48 service members both prior-to and following deployment to conflict zones. Half of the subjects returned with Post-traumatic Stress Disorder (PTSD), while the other half did not.

Project description:The molecular factors involved in the development of Post-Traumatic Stress Disorder (PTSD) remain poorly understood. Previous transcriptomic studies investigating the mechanisms of PTSD apply targeted approaches to identify individual genes under a cross-sectional framework lack a holistic view of the behaviours and properties of these genes at the system-level. Here we sought to apply an unsupervised gene-network based approach to a prospective experimental design using whole-transcriptome RNA-Seq gene expression from peripheral blood leukocytes of U.S. Marines (N=188), obtained both pre- and post-deployment to conflict zones. We identified discrete groups of co-regulated genes (i.e., co-expression modules) and tested them for association to PTSD. We identified one module at both pre- and post-deployment containing putative causal signatures for PTSD development displaying an over-expression of genes enriched for functions of innate-immune response and interferon signalling (Type-I and Type-II). Importantly, these results were replicated in a second non-overlapping independent dataset of U.S. Marines (N=96), further outlining the role of innate immune and interferon signalling genes within co-expression modules to explain at least part of the causal pathophysiology for PTSD development. A second module, consequential of trauma exposure, contained PTSD resiliency signatures and an over-expression of genes involved in hemostasis and wound responsiveness suggesting that chronic levels of stress impair proper wound healing during/after exposure to the battlefield while highlighting the role of the hemostatic system as a clinical indicator of chronic-based stress. These findings provide novel insights for early preventative measures and advanced PTSD detection, which may lead to interventions that delay or perhaps abrogate the development of PTSD. We used RNA-Sequencing gene expression to characterize both prognostic and diagnostic molecular signatures associated to PTSD risk and PTSD status compared to control subjects. Peripheral blood luekocytes gene expression was subject to transcriptional analysis for 94 service members both prior-to and following-deployment to conflict zones. Half of the subjects returned with Post-traumatic stress disorder (PTSD), while the other half did not.

Project description:Maternal smoking has a severe negative effect on all stages of pregnancy that in consequence impairs fetal growth and development. Tobacco smoke-related defects are well established at the clinical level; however, little is known about molecular mechanisms underlying these pathological conditions. We thus employed a genomic approach to determine transcriptome alterations induced by maternal smoking in pregnancy. We assayed gene expression profiles in peripheral blood (M) leukocytes and placentas (PL) of pregnant smokers and those without significant exposure, and in cord blood (D) leukocytes of their babies. Comparative analyses defined significant deregulation of 193 genes in M cells, 329 genes in placentas, and 49 genes in D cells of smokers. These genes were mainly involved in xenobiotic metabolism, oxidative stress, inflammation, immunity, hematopoiesis, trophoblast differentiation, and vascularization. Functional annotation of the deregulated genes outlined processes and pathways affected by tobacco smoke. In smoker newborns, we identified several deregulated pathways associated with autoimmune diseases. The study demonstrates a limited ability of placenta to modulate toxic effects of maternal tobacco use at the gene expression level. Blood and placental samples were obtained from 91 women who gave birth to a baby in the Ceske Budejovice Hospital from November 2008 to March 2009. The study was approved by the Local Institutional Review Board. All participants provided written informed consent and completed an extensive questionnaire on pregnancy history (medication, diseases), delivery course, newborn characteristics and life style (smoking, diet, alcohol drinking, area of residency). Only subjects who underwent vaginal delivery were included in the study. Based on smoking history, the women were divided into two groups, “smokers” (N=20) and “non-smokers” (N=52), while passive smokers (N=19) were excluded from the study. Smoking status was further confirmed by detection of excessive plasma levels of cotinine (the major nicotine metabolite) in maternal blood.

Project description:Air pollutants including particulate matter (PM) and chemicals adsorbed onto PM pose a serious threat to human health. In this study, we analyzed the ability of PM to induce diverse gene expression profile modulation after chronic exposure in subjects living in two regions of the Czech Republic differing in levels and sources of the air pollution. We also considered impact of different seasonal conditions on concentrations and compositions of PM. Blood samples of 312 subjects from polluted Ostrava city and 154 controls from Prague city were collected in winter 2009, summer 2009 and winter 2010. The highest concentrations of air pollutants were detected in winter 2010 when the subjects were exposed to: PM of aerodynamic diameter < 2.5 M-BM-5m (70 vs. 44.9 M-BM-5g/m3); benzo[a]pyrene (9.02 vs. 2.56 ng/m3) and benzene (10.2 vs. 5.5 M-BM-5g/m3) in Ostrava and Prague, respectively. Global gene expression analysis of total RNA extracted from leukocytes was performed using whole genome microarrays (Illumina). The expression of selected genes was verified by quantitative real-time PCR (qRT-PCR). Despite lower concentrations of air pollutants we found a higher number of differentially expressed genes and affected KEGG pathways in subjects from Prague. In both locations we observed differences between seasons. The qRT-PCR analysis showed a significant decrease in expression of APEX, ATM, FAS, GSTM1, IL1B and RAD21 in subjects from Ostrava, in a comparison of winter 2010 and summer 2009. In Prague, an increase in gene expression was observed for GADD45A and PTGS2. In conclusion, high concentrations of pollutants in Ostrava do not increase the number of differentially expressed genes. This may be explained by adaption of humans to chronic exposure to air pollution. Total RNA was extracted from leukocytes of total of 154 control subjects and 312 subjects exposed to heavy air pollution. The samples were collected in three seasons (winter 2009, summer 2009, winter 2010) with different levels of air pollution. Most of the subjects were sampled repeatedly; however, some of them joined the study in summer 2009 or winter 2010.

Project description:Angelman syndrome (AS) and interstitial duplication 15q autism (int dup(15)) are reciprocal genomic disorders caused by maternal deletion or duplication of the 15q11.2-q13 region. While AS is caused by maternal loss of 15q and maternal duplications of 15q can cause autism implicating the maternally expressed UBE3A gene in these phenotypes. We investigated chromatin and gene expression changes in blood and cell lines from three int dup(15) and three reciprocal AS deletion subjects to identify global genomic and gene expression changes that may influence both the AS and autism phenotypes. Using formaldehyde-assisted isolation of regulatory elements (FAIRE) we identified 1104 regions of differential open chromatin in AS deletion and 2344 regions int dup(15) indicating changes in chromatin could influence gene expression in these regions. Microarray analysis revealed 1225 genes that were elevated in AS deletion vs int dup(15) and 976 genes that were elevated in int dup(15) vs AS deletion PBMC (pvalue<0.05). Significant differences in expression were found for genes at the 15q locus like UBE3A, ATP10A and HERC2. A larger set of genes involved in chromatin remodeling, DNA repair and neurogenesis were found, at FAIRE peaks in AS deletion samples but had increased transcription in int dup(15) samples. There was a significant enhancement for genes with FOXP1 binding sites in the int dup(15) gene set and elevated FOXP1 protein could be detected in the nucleus of int dup(15) as compared to AS deletion cell lines. This analysis provides the first insights into transcriptional changes which may unveil new sets of genes and pathways contributing to both AS and autism pathogenesis. Gene expression was performed using 100ng of total RNA from each subject as starting material for amplification and cRNA synthesis in accordance Affymetrix protocols (http://tinyurl.com/3j7dcp6). Hybridizations were performed to the Affy HumanGene_st_v1 chip and the signal data normalized using internal chip controls. Normalized expression data was then exported to a text file for subsequent expression analysis using the EXPANDER software analysis suite.

Project description:Sub-thalamic deep brain stimulation (DBS) reversibly modulates ParkinsonM-bM-^@M-^Ys disease (PD) motor symptoms, providing an unusual opportunity to compare leukocyte transcripts in the same subjects before and after neurosurgery and after disconnecting the stimulus (ON-and OFF-stimulus). Here, we report rapid stimulus-induced and largely reversible changes in PD leukocyte transcripts, which were larger in scope than the disease-induced changes. These transcript changes classified advanced pre- from post-surgery PD patients and discriminated patients from controls. Moreover, the extent of changes correlated with the neurological efficacy of the DBS neurosurgery, and covered both regulatory pathways and individual transcript changes, e.g. SNCA, PARK7 and the splicing factor SFRS1. Following 1 hour OFF-stimulus, these changes were largely reversed. We extracted from these differences a modified transcripts signature which discriminated controls from advanced PD patients, pre- from post-surgery and ON-from OFF-stimulus conditions. A further gene-list independent analysis detected reversed pathways. Our findings suggest future uses of this approach and the discovered molecular signature for early diagnostics of PD and for identifying novel targets for therapeutic intervention in this and other DBS-treatable neurological diseases. 27 Total samples were analyzed. Study design included four conditions. PD patients (n=7) leukocyte blood samples were examined at 3 time points, and healthy control subjects (n=6) were examined once each. Samples were taken 1 day prior to sub-thalamic nucleous (STN) DBS treatment, several months after STN-DBS treatment upon optimal stimulation and following one hour electrical stimulation cessation. The off stimulation caused recruitment of the disease symptoms as measured by the Unified Parkinson's Disease Rating Scale motor section (UPDRS-III). The different stages are designated: S1 (pre-treatment), S2 (post STN-DBS) and S3 (upon off stimulation). All patients were on dopamine replacement therapy (DRT) when examined pre- and post-DBS off stimulation (albeit with reduced therapy dose post-DBS). To reduce biological variability among the samples which is not related to the study, only male subjects were included in this study. Samples from six age- and gender- matched healthy control subjects served to detect disease modified transcripts and for pre- and post- treatment comparisons. The study was approved by the human review board at the Hadassah University Hospital, Ein-Kerem (no. 6-07.09.07) in accordance with the Declaration of Helsinki. All study participants signed informed consent.

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Gene Networks Specific for Innate Immunity Define Post-traumatic Stress Disorder

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