Transcriptional Control of Monocyte Gene Expression in Post-Traumatic Stress Disorder

O’Donovan, Aoife; Sun, Bing; Cole, Steve W.; Rempel, Hans; Lenoci, Maryann; Pulliam, Lynn; Neylan, Thomas C.

doi:10.1155/2011/560572

Cited by 120 publications

(99 citation statements)

References 62 publications

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“…Compared with PBMCs from MR rhesus macaques, those from peer-reared animals (both SPR and PR) show enhanced expression of genes involved in inflammation and T-lymphocyte activation and reduced expression of genes involved in type I IFN-mediated innate antiviral responses and other pathogen-specific innate antimicrobial responses. This pattern of enhanced inflammatory gene expression and inhibited antiviral gene expression parallels the conserved transcriptional response to adversity (CTRA) observed in previous correlational studies of humans confronting adverse life circumstances (9,(27)(28)(29)(30)(31)(32)43). The experimental manipulation of early life social conditions in this study demonstrates that social adversity can play a causal role in activating CTRA dynamics and can do so during the earliest stages of postnatal immune system development.…”

Section: Discussionsupporting

confidence: 82%

“…To determine whether these adult transcriptional alterations might potentially stem from a biological reprogramming of the developing immune system during early life, we analyze the genome-wide transcriptional profile of circulating leukocytes in infant rhesus macaques (Macaca mulatta) after 4 mo of experimentally imposed social adversity (peer vs. maternal rearing) (26). To the extent that adverse social conditions become rapidly embedded into the gene regulatory regime of the developing immune system, we expect that (i) surrogate/peer-rearing (SPR) and peer-rearing (PR) conditions increase the expression of genes involved in inflammation while decreasing expression of genes involved in type I IFN-mediated innate antiviral responses [i.e., the "conserved transcriptional response to adversity" previously observed in adults (9,(27)(28)(29)(30)(31)(32)] and (ii) these effects are structured by transcription control pathways linked to stress-responsive "social signal transduction" pathways such as the sympathetic nervous system (SNS) and hypothalamus-pituitary-adrenal (HPA) axis (10,13,17,32). These hypotheses are tested by coupling microarray-based assessment of the entire macaque transcriptome with recent advances in computational bioinformatics (33) and multiple-hypothesis testing (34)(35)(36) to map large ensembles of differentially expressed genes into a small number of higher-order biological themes regarding their regulatory causes (e.g., transcription factor activity) (37), cellular contexts (e.g., originating leukocyte subtype) (30), and functional consequences (e.g., Gene Ontology functional annotations) (38).…”

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confidence: 99%

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Transcriptional modulation of the developing immune system by early life social adversity

Cole¹,

Conti

Arevalo³

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

187

174

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To identify molecular mechanisms by which early life social conditions might influence adult risk of disease in rhesus macaques (Macaca mulatta), we analyze changes in basal leukocyte gene expression profiles in 4-mo-old animals reared under adverse social conditions. Compared with the basal condition of maternal rearing (MR), leukocytes from peer-reared (PR) animals and PR animals provided with an inanimate surrogate mother (surrogate/peer reared, SPR) show enhanced expression of genes involved in inflammation, cytokine signaling, and T-lymphocyte activation, and suppression of genes involved in several innate antimicrobial defenses including type I interferon (IFN) antiviral responses. Promoter-based bioinformatic analyses implicate increased activity of CREB and NF-κB transcription factors and decreased activity of IFN response factors (IRFs) in structuring the observed differences in gene expression. Transcript origin analyses identify monocytes and CD4+ T lymphocytes as primary cellular mediators of transcriptional up-regulation and B lymphocytes as major sources of down-regulated genes. These findings show that adverse social conditions can become embedded within the basal transcriptome of primate immune cells within the first 4 mo of life, and they implicate sympathetic nervous system-linked transcription control pathways as candidate mediators of those effects and potential targets for health-protective intervention.stress | social genomics | gene regulation E xposure to adverse social environments during early life is associated with increased risk of disease in adulthood (1-5), but the biological mechanisms producing such effects remain poorly understood. One possible explanation suggests that neural and endocrine responses to adversity in childhood affect the development of health-relevant molecular systems (i.e., a "defensive programming" of the developing body) (4, 6-10), rendering the body more vulnerable to subsequent pathogen challenges in adulthood (11,12). Given the transience of most neuroendocrine responses, however, it remains unclear how the extraorganismic social conditions that do "get into the body" during early life could "stay there" over decades to impact the risk of disease in adulthood (13).One molecular mechanism that could potentially create a persisting biological impact of early life socio-environmental conditions involves the complex systems behavior of the gene transcriptional networks that govern cell growth, differentiation, and function (14, 15). Gene regulatory networks show dynamic landscapes in which the system's responses to external perturbations converge on a small number of stable "attractor" modes that can subsequently self-perpetuate (16). These self-perpetuating dynamics are sustained in part by the fact that the mRNA "output" of the system at one point in time (i.e., the genome-wide transcriptional profile) constitutes an "input" to the system at subsequent time points because translated mRNA shapes the cell's response to future environments (17). Mathematical mo...

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Section: Discussionsupporting

confidence: 82%

mentioning

confidence: 99%

Transcriptional modulation of the developing immune system by early life social adversity

Cole¹,

Conti

Arevalo³

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

187

174

View full text Add to dashboard Cite

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“…In conjunction with the analyses of transcription factor activity, these results suggest that the divergent gene expression profiles observed in hedonic and eudaimonic well-being are mediated by activation of distinct receptor systems within a fixed set of environmentally responsive cell types (33). These findings mirror results from previous studies of adverse experience in identifying a similar set of target cells (34,36,41,42), with eudaimonic well-being in particular showing a reversal of CTRA-related transcription factor dynamics (12,33). These results identify specific psychological, cellular, and molecular targets for future analyses of the social signal transduction pathways that mediate the prospective health advantages of psychological well-being (1)(2)(3)(4)(5)(6)(7)(8)(9)(10)(11).…”

Section: Discussionsupporting

confidence: 82%

A functional genomic perspective on human well-being

Fredrickson

Grewen

Coffey

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

396

444

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To identify molecular mechanisms underlying the prospective health advantages associated with psychological well-being, we analyzed leukocyte basal gene expression profiles in 80 healthy adults who were assessed for hedonic and eudaimonic well-being, as well as potentially confounded negative psychological and behavioral factors. Hedonic and eudaimonic well-being showed similar affective correlates but highly divergent transcriptome profiles. Peripheral blood mononuclear cells from people with high levels of hedonic well-being showed up-regulated expression of a stress-related conserved transcriptional response to adversity (CTRA) involving increased expression of proinflammatory genes and decreased expression of genes involved in antibody synthesis and type I IFN response. In contrast, high levels of eudaimonic well-being were associated with CTRA down-regulation. Promoter-based bioinformatics implicated distinct patterns of transcription factor activity in structuring the observed differences in gene expression associated with eudaimonic well-being (reduced NF-κB and AP-1 signaling and increased IRF and STAT signaling). Transcript origin analysis identified monocytes, plasmacytoid dendritic cells, and B lymphocytes as primary cellular mediators of these dynamics. The finding that hedonic and eudaimonic well-being engage distinct gene regulatory programs despite their similar effects on total well-being and depressive symptoms implies that the human genome may be more sensitive to qualitative variations in well-being than are our conscious affective experiences.

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“…Among the heterogeneous leukocyte population, bioinformatic decomposition identified monocytes and dendritic cells as most responsive to changes in socioenvironmental conditions . Analysis of isolated leukocyte subpopulations confirmed that monocytes mediate many of the transcriptional effects of social adversity, eg, of traumatic stress (O'Donovan et al, 2011), imminent bereavement, or chronic stress in caregivers of terminally ill patients (Miller et al, , 2014. Furthermore, there is evidence for a link between inflammation and early adversity (Baumeister et al, 2015).…”

Section: Introductionmentioning

confidence: 91%

Altered Stress-Induced Regulation of Genes in Monocytes in Adults with a History of Childhood Adversity

Schwaiger

Grinberg

Moser

et al. 2016

Neuropsychopharmacol

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Exposure to serious or traumatic events early in life can lead to persistent alterations in physiological stress response systems, including enhanced cross talk between the neuroendocrine and immune system. These programming effects may be mechanistically involved in mediating the effects of adverse childhood experience on disease risk in adulthood. We investigated hormonal and genome-wide mRNA expression responses in monocytes to acute stress exposure, in a sample of healthy adults (n = 30) with a history of early childhood adversity, and a control group (n = 30) without trauma experience. The early adversity group showed altered hypothalamus-pituitaryadrenal axis responses to stress, evidenced by lower ACTH and cortisol responses. Analyses of gene expression patterns showed that stress-responsive transcripts were enriched for genes involved in cytokine activity, cytokine-cytokine receptor interaction, chemokine activity, and G-protein coupled receptor binding. Differences between groups in stress-induced regulation of gene transcription were observed for genes involved in steroid binding, hormone activity, and G-protein coupled receptor binding. Transcription factor binding motif analysis showed an increased activity of pro-inflammatory upstream signaling in the early adversity group. We also identified transcripts that were differentially correlated with stress-induced cortisol increases between the groups, enriched for genes involved in cytokine-cytokine receptor interaction and glutamate receptor signaling. We suggest that childhood adversity leads to persistent alterations in transcriptional control of stress-responsive pathways, which-when chronically or repeatedly activated-might predispose individuals to stress-related psychopathology.

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Transcriptional Control of Monocyte Gene Expression in Post-Traumatic Stress Disorder

Cited by 120 publications

References 62 publications

Transcriptional modulation of the developing immune system by early life social adversity

Transcriptional modulation of the developing immune system by early life social adversity

A functional genomic perspective on human well-being

Altered Stress-Induced Regulation of Genes in Monocytes in Adults with a History of Childhood Adversity

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