scholarly journals Social status alters chromatin accessibility and the gene regulatory response to glucocorticoid stimulation in rhesus macaques

2018 ◽  
Author(s):  
Noah Snyder-Mackler ◽  
Joaquín Sanz ◽  
Jordan N. Kohn ◽  
Tawni N. Voyles ◽  
Roger Pique-Regi ◽  
...  
Keyword(s):  
Gene Expression ◽  
Gene Regulation ◽  
Social Status ◽  
Molecular Mechanisms ◽  
Immune Cell ◽  
Rhesus Macaques ◽  
Dominance Rank ◽  
Chromatin Accessibility ◽  
High Status ◽  
Cell Gene

ABSTRACTLow social status is an important predictor of disease susceptibility and mortality risk in humans and other social mammals. These effects are thought to stem in part from dysregulation of the glucocorticoid (GC)-mediated stress response. However, the molecular mechanisms that connect low social status and GC dysregulation to downstream health outcomes remain elusive. Here, we used an in vitro glucocorticoid challenge to investigate the consequences of experimentally manipulated social status (i.e., dominance rank) for immune cell gene regulation in female rhesus macaques, using paired control and GC-treated peripheral blood mononuclear cell samples. We show that social status not only influences immune cell gene expression, but also chromatin accessibility at hundreds of regions in the genome. Social status effects on gene expression were less pronounced following GC treatment than under control conditions. In contrast, social status effects on chromatin accessibility were stable across conditions, resulting in an attenuated relationship between social status, chromatin accessibility, and gene expression post-GC exposure. Regions that were more accessible in high status animals and regions that become more accessible following GC treatment were enriched for a highly concordant set of transcription factor binding motifs, including motifs for the glucocorticoid receptor co-factor AP-1. Together, our findings support the hypothesis that social status alters the dynamics of GC-mediated gene regulation, and identify chromatin accessibility as a mechanism involved in social stress-driven GC resistance. More broadly, they emphasize the context-dependent nature of social status effects on gene regulation and implicate epigenetic remodeling of chromatin accessibility as a contributing factor.

scholarly journals Social status alters chromatin accessibility and the gene regulatory response to glucocorticoid stimulation in rhesus macaques

2018 ◽  
Vol 116 (4) ◽  
pp. 1219-1228 ◽  
Author(s):  
Noah Snyder-Mackler ◽  
Joaquín Sanz ◽  
Jordan N. Kohn ◽  
Tawni Voyles ◽  
Roger Pique-Regi ◽  
...  
Keyword(s):  
Gene Expression ◽  
Gene Regulation ◽  
Social Status ◽  
Molecular Mechanisms ◽  
Immune Cell ◽  
Rhesus Macaques ◽  
Dominance Rank ◽  
Chromatin Accessibility ◽  
High Status ◽  
Cell Gene

Low social status is an important predictor of disease susceptibility and mortality risk in humans and other social mammals. These effects are thought to stem in part from dysregulation of the glucocorticoid (GC)-mediated stress response. However, the molecular mechanisms that connect low social status and GC dysregulation to downstream health outcomes remain elusive. Here, we used an in vitro GC challenge to investigate the consequences of experimentally manipulated social status (i.e., dominance rank) for immune cell gene regulation in female rhesus macaques, using paired control and GC-treated peripheral blood mononuclear cell samples. We show that social status not only influences immune cell gene expression but also chromatin accessibility at hundreds of regions in the genome. Social status effects on gene expression were less pronounced following GC treatment than under control conditions. In contrast, social status effects on chromatin accessibility were stable across conditions, resulting in an attenuated relationship between social status, chromatin accessibility, and gene expression after GC exposure. Regions that were more accessible in high-status animals and regions that become more accessible following GC treatment were enriched for a highly concordant set of transcription factor binding motifs, including motifs for the GC receptor cofactor AP-1. Together, our findings support the hypothesis that social status alters the dynamics of GC-mediated gene regulation and identify chromatin accessibility as a mechanism involved in social stress-driven GC resistance. More broadly, they emphasize the context-dependent nature of social status effects on gene regulation and implicate epigenetic remodeling of chromatin accessibility as a contributing factor.

scholarly journals Dominance rank-associated immune gene expression is widespread, sex-specific, and a precursor to high social status in wild male baboons

2018 ◽  
Author(s):  
Amanda J. Lea ◽  
Mercy Y. Akinyi ◽  
Ruth Nyakundi ◽  
Peter Mareri ◽  
Fred Nyundo ◽  
...  
Keyword(s):  
Gene Expression ◽  
Gene Regulation ◽  
Social Status ◽  
Rhesus Macaques ◽  
Dominance Rank ◽  
Immune Gene ◽  
High Status ◽  
Social Hierarchies ◽  
The Relationship ◽  
High Social Status

ABSTRACTIn humans and other hierarchical species, social status is tightly linked to variation in health and fitness-related traits. Experimental manipulations of social status in female rhesus macaques suggest that this relationship is partially explained by status effects on immune gene regulation. However, social hierarchies are established and maintained in different ways across species: while some are based on kin-directed nepotism, others emerge from direct physical competition. We investigated how this variation influences the relationship between social status and immune gene regulation in wild baboons, where hierarchies in males are based on fighting ability but female hierarchies are nepotistic. We measured rank-related variation in gene expression levels in adult baboons of both sexes at baseline and in response to ex vivo stimulation with the bacterial endotoxin lipopolysaccharide (LPS). We identified >2000 rank- associated genes in males, an order of magnitude more than in females. In males, high status predicted increased expression of genes involved in innate immunity and preferential activation of the NFkB-mediated pro-inflammatory pathway, a pattern previously associated with low status in female rhesus macaques. Using Mendelian randomization, we reconcile these observations by demonstrating that high status-associated gene expression patterns are precursors, not consequences, of high social status in males, in support of the idea that physiological condition determines who attains high rank. Together, our work provides the first test of the relationship between social status and immune gene regulation in wild primates. It also emphasizes the importance of social context in shaping the relationship between social status and immune function.SIGNIFICANCESocial status predicts fitness outcomes in social animals, motivating efforts to understand its physiological causes and consequences. We investigated the relationship between social status and immune gene expression in wild baboons, where female status is determined by kinship but male status is determined by fighting ability. We uncover pervasive status-gene expression associations in males, but not females. High status males exhibit high levels of pro-inflammatory gene expression, in contrast to previous findings in hierarchies that are not competitively determined. Using Mendelian randomization, we show that this status-associated variation precedes dominance rank attainment: males who compete successfully for high status are already immunologically distinct. The nature of social hierarchies thus fundamentally shapes the relationship between social status and immune function.

scholarly journals Dominance rank-associated gene expression is widespread, sex-specific, and a precursor to high social status in wild male baboons

2018 ◽  
Vol 115 (52) ◽  
pp. E12163-E12171 ◽  
Author(s):  
Amanda J. Lea ◽  
Mercy Y. Akinyi ◽  
Ruth Nyakundi ◽  
Peter Mareri ◽  
Fred Nyundo ◽  
...  
Keyword(s):  
Gene Expression ◽  
Gene Regulation ◽  
Social Status ◽  
Rhesus Macaques ◽  
Immune Gene ◽  
High Status ◽  
Female Rhesus ◽  
The Relationship ◽  
High Social Status ◽  
Female Rhesus Macaques

In humans and other hierarchical species, social status is tightly linked to variation in health and fitness-related traits. Experimental manipulations of social status in female rhesus macaques suggest that this relationship is partially explained by status effects on immune gene regulation. However, social hierarchies are established and maintained in different ways across species: While some are based on kin-directed nepotism, others emerge from direct physical competition. We investigated how this variation influences the relationship between social status and immune gene regulation in wild baboons, where hierarchies in males are based on fighting ability but female hierarchies are nepotistic. We measured rank-related variation in gene expression levels in adult baboons of both sexes at baseline and in response to ex vivo stimulation with the bacterial endotoxin lipopolysaccharide (LPS). We identified >2,000 rank-associated genes in males, an order of magnitude more than in females. In males, high status predicted increased expression of genes involved in innate immunity and preferential activation of the NF-κB–mediated proinflammatory pathway, a pattern previously associated with low status in female rhesus macaques. Using Mendelian randomization, we reconcile these observations by demonstrating that high status-associated gene expression patterns are precursors, not consequences, of high social status in males, in support of the idea that physiological condition determines who attains high rank. Together, our work provides a test of the relationship between social status and immune gene regulation in wild primates. It also emphasizes the importance of social context in shaping the relationship between social status and immune function.

scholarly journals Social history and exposure to pathogen signals modulate social status effects on gene regulation in rhesus macaques

2019 ◽  
Vol 117 (38) ◽  
pp. 23317-23322 ◽  
Author(s):  
Joaquín Sanz ◽  
Paul L. Maurizio ◽  
Noah Snyder-Mackler ◽  
Noah D. Simons ◽  
Tawni Voyles ◽  
...  
Keyword(s):  
Gene Expression ◽  
Social Status ◽  
Social History ◽  
Immune Cell ◽  
Rhesus Macaques ◽  
Expression Patterns ◽  
Social Experience ◽  
Type I ◽  
Gene Expression Response ◽  
Expression Of Genes

Social experience is an important predictor of disease susceptibility and survival in humans and other social mammals. Chronic social stress is thought to generate a proinflammatory state characterized by elevated antibacterial defenses and reduced investment in antiviral defense. Here we manipulated long-term social status in female rhesus macaques to show that social subordination alters the gene expression response to ex vivo bacterial and viral challenge. As predicted by current models, bacterial lipopolysaccharide polarizes the immune response such that low status corresponds to higher expression of genes in NF-κB–dependent proinflammatory pathways and lower expression of genes involved in the antiviral response and type I IFN signaling. Counter to predictions, however, low status drives more exaggerated expression of both NF-κB– and IFN-associated genes after cells are exposed to the viral mimic Gardiquimod. Status-driven gene expression patterns are linked not only to social status at the time of sampling, but also to social history (i.e., past social status), especially in unstimulated cells. However, for a subset of genes, we observed interaction effects in which females who fell in rank were more strongly affected by current social status than those who climbed the social hierarchy. Taken together, our results indicate that the effects of social status on immune cell gene expression depend on pathogen exposure, pathogen type, and social history—in support of social experience-mediated biological embedding in adulthood, even in the conventionally memory-less innate immune system.

scholarly journals Social Adversity Impacts on the Rhesus Macaque Immune System Resemble Those of Aging

2020 ◽  
Vol 4 (Supplement_1) ◽  
pp. 925-925
Author(s):  
Mitchell Sanchez-Rosado ◽  
Noah Snyder-Mackler ◽  
Lauren Brent ◽  
James Higham ◽  
Clare Kimock ◽  
...  
Keyword(s):  
Immune System ◽  
T Cell ◽  
Social Status ◽  
Immune Cell ◽  
Rhesus Macaques ◽  
Natural Aging ◽  
High Status ◽  
Regulatory Cells ◽  
T Regulatory Cell ◽  
Social Adversity

Abstract Social adversity can impact immune function and is associated with increased morbidity and mortality. Many of these immune-related changes resemble the effects of the natural aging process. To date, little is known about the effects of social adversity on the immune system change across the lifetime. Here, we investigated how aging and social adversity (measured as social status) impact immune cell proportions. We performed flow cytometry on peripheral whole blood from a population of free-ranging rhesus macaques to quantify changes on immune cell proportions across the lifespan (n=99) and across different social statuses (n=53). Overall, we found that high adversity recapitulated the effects of aging. We found significant shared decreases in CD3+/CD4+ T cell proportions and corresponding increases in CD3+/CD8+ T cell proportions between individuals of older ages and low social status. These findings suggest that social adversity has similar effects to aging on T cell proportions, possibly affecting the T cell component of the immune response. In contrast, CD3+/CD4+/CD25+ T regulatory cell proportions increased with age, which is typical of normal aging. Contrary to our expectations, these cells were less abundant in low status individuals, indicating some overall regulatory immune deficits specific to lower status individuals. CD3+/CD8+/CD25+ T regulatory cells, which contribute to self-tolerance, were higher in high status individuals, suggesting that overall primary immune regulatory cells can be affected by social adversity and impair the regulation of inflammation. We provide evidence that social adversity alters immune cell proportions, implicating it in the development of inflammatory and/or aging-related diseases.

scholarly journals Social history and exposure to pathogen signals modulate social status effects on gene regulation in rhesus macaques

2019 ◽  
Author(s):  
Joaquin Sanz ◽  
Paul L. Maurizio ◽  
Noah Snyder-Mackler ◽  
Noah D. Simons ◽  
Tawni Voyles ◽  
...  
Keyword(s):  
Gene Expression ◽  
Social Status ◽  
Social History ◽  
Social Stress ◽  
Immune Cell ◽  
Rhesus Macaques ◽  
Expression Patterns ◽  
Type I ◽  
Gene Expression Response ◽  
Expression Of Genes

AbstractSocial experiences are an important predictor of disease susceptibility and survival in humans and other social mammals. Chronic social stress is thought to generate a pro-inflammatory state characterized by elevated antibacterial defenses and reduced investment in antiviral defense. Here, we manipulated long-term social status in female rhesus macaques to show that social subordination alters the gene expression response to ex vivo bacterial and viral challenge. As predicted by current models, bacterial lipopolysaccharide polarizes the immune response such that low status corresponds to higher expression of genes in NF-κB-dependent pro-inflammatory pathways and lower expression of genes involved in the antiviral response and type I interferon (IFN) signaling. Counter to predictions, however, low status drives more exaggerated expression of both NF-κB and IFN-associated genes after cells are exposed to the viral mimic Gardiquimod. Status-driven gene expression patterns are not only linked to social status at the time of sampling, but also to social history (i.e., past social status), especially in unstimulated cells. However, for a subset of genes, we observed interaction effects in which females who fell in rank were more strongly affected by current social status than those who climbed the social hierarchy. Together, our results indicate that the effects of social status on immune cell gene expression depend on pathogen exposure, pathogen type, and social history – in support of social experience-mediated biological embedding in adulthood, even in the conventionally memory-less innate immune system.

scholarly journals Agonism and grooming behavior explain social status effects on physiology and gene regulation in rhesus macaques

2021 ◽  
Author(s):  
Noah D Simons ◽  
Vasiliki Michopoulos ◽  
Mark Wilson ◽  
Luis B Barreiro ◽  
Jenny Tung
Keyword(s):  
Gene Regulation ◽  
Social Status ◽  
Lived Experience ◽  
Rhesus Macaques ◽  
Dominance Rank ◽  
Experimental Studies ◽  
Experimental Manipulation ◽  
Affiliative Behavior ◽  
Behavioral Interactions ◽  
Physiological Outcomes

Variation in social status predicts molecular, physiological, and life history outcomes across a broad range of species, including our own. Experimental studies indicate that some of these relationships persist even when the physical environment is held constant. Here, we draw on data sets from one such study-experimental manipulation of dominance rank in captive female rhesus macaques-to investigate how social status shapes the lived experience of these animals to alter gene regulation, glucocorticoid physiology, and mitochondrial DNA phenotypes. We focus specifically on dominance rank-associated dimensions of the social environment, including both competitive and affiliative interactions. Our results show that simple summaries of rank-associated behavioral interactions are often better predictors of molecular and physiological outcomes than dominance rank itself. However, while measures of immune function are best explained by agonism rates, glucocorticoid-related phenotypes tend to be more closely linked to affiliative behavior. We conclude that dominance rank serves as a useful summary for investigating social environmental effects on downstream outcomes. Nevertheless, the behavioral interactions that define an individual's daily experiences reveal the proximate drivers of social status-related differences, and are especially relevant for understanding why individuals who share the same social status sometimes appear physiologically distinct.

scholarly journals Gut microbiota has a widespread and modifiable effect on host gene regulation

2017 ◽  
Author(s):  
Allison L Richards ◽  
Amanda L Muehlbauer ◽  
Adnan Alazizi ◽  
Michael B Burns ◽  
Anthony Findley ◽  
...  
Keyword(s):  
Gene Expression ◽  
Gene Regulation ◽  
Epithelial Cells ◽  
Gut Microbiota ◽  
Complex Traits ◽  
Molecular Mechanisms ◽  
Expression Profiles ◽  
Chromatin Accessibility ◽  
Host Cells ◽  
Host Genes

AbstractVariation in gut microbiome is associated with wellness and disease in humans, yet the molecular mechanisms by which this variation affects the host are not well understood. A likely mechanism is through changing gene regulation in interfacing host epithelial cells. Here, we treated colonic epithelial cells with live microbiota from five healthy individuals and quantified induced changes in transcriptional regulation and chromatin accessibility in host cells. We identified over 5,000 host genes that change expression, including 588 distinct associations between specific taxa and host genes. The taxa with the strongest influence on gene expression alter the response of genes associated with complex traits. Using ATAC-seq, we show that a subset of these changes in gene expression are likely the result of changes in host chromatin accessibility and transcription factor binding induced by exposure to gut microbiota. We then created a manipulated microbial community with titrated doses ofCollinsella, demonstrating that both natural and controlled microbiome composition leads to distinct, and predictable, gene expression profiles in host cells. Together, our results suggest that specific microbes play an important role in regulating expression of individual host genes involved in human complex traits. The ability to fine tune the expression of host genes by manipulating the microbiome suggests future therapeutic routes.

scholarly journals Agonism and grooming behaviour explain social status effects on physiology and gene regulation in rhesus macaques

2022 ◽  
Vol 377 (1845) ◽  
Author(s):  
Noah D. Simons ◽  
Vasiliki Michopoulos ◽  
Mark Wilson ◽  
Luis B. Barreiro ◽  
Jenny Tung
Keyword(s):  
Gene Regulation ◽  
Social Status ◽  
Lived Experience ◽  
Rhesus Macaques ◽  
Dominance Rank ◽  
Experimental Studies ◽  
Experimental Manipulation ◽  
Behavioural Interactions ◽  
Physiological Outcomes ◽  
Social Environmental

Variation in social status predicts molecular, physiological and life-history outcomes across a broad range of species, including our own. Experimental studies indicate that some of these relationships persist even when the physical environment is held constant. Here, we draw on datasets from one such study—experimental manipulation of dominance rank in captive female rhesus macaques—to investigate how social status shapes the lived experience of these animals to alter gene regulation, glucocorticoid physiology and mitochondrial DNA phenotypes. We focus specifically on dominance rank-associated dimensions of the social environment, including both competitive and affiliative interactions. Our results show that simple summaries of rank-associated behavioural interactions are often better predictors of molecular and physiological outcomes than dominance rank itself. However, while measures of immune function are best explained by agonism rates, glucocorticoid-related phenotypes tend to be more closely linked to affiliative behaviour. We conclude that dominance rank serves as a useful summary for investigating social environmental effects on downstream outcomes. Nevertheless, the behavioural interactions that define an individual's daily experiences reveal the proximate drivers of social status-related differences and are especially relevant for understanding why individuals who share the same social status sometimes appear physiologically distinct. This article is part of the theme issue ‘The centennial of the pecking order: current state and future prospects for the study of dominance hierarchies’.

scholarly journals Mapping chromatin accessibility and active regulatory elements reveals pathological mechanisms in human gliomas

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Karolina Stępniak ◽  
Magdalena A. Machnicka ◽  
Jakub Mieczkowski ◽  
Anna Macioszek ◽  
Bartosz Wojtaś ◽  
...  
Keyword(s):  
Gene Expression ◽  
Chromatin Structure ◽  
Molecular Mechanisms ◽  
Genome Mapping ◽  
Malignant Gliomas ◽  
Regulatory Elements ◽  
Chromatin Accessibility ◽  
Multiple Tumor ◽  
Genes Encoding ◽  
Methylation Patterns

AbstractChromatin structure and accessibility, and combinatorial binding of transcription factors to regulatory elements in genomic DNA control transcription. Genetic variations in genes encoding histones, epigenetics-related enzymes or modifiers affect chromatin structure/dynamics and result in alterations in gene expression contributing to cancer development or progression. Gliomas are brain tumors frequently associated with epigenetics-related gene deregulation. We perform whole-genome mapping of chromatin accessibility, histone modifications, DNA methylation patterns and transcriptome analysis simultaneously in multiple tumor samples to unravel epigenetic dysfunctions driving gliomagenesis. Based on the results of the integrative analysis of the acquired profiles, we create an atlas of active enhancers and promoters in benign and malignant gliomas. We explore these elements and intersect with Hi-C data to uncover molecular mechanisms instructing gene expression in gliomas.

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