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

Snyder‐Mackler, Noah; Sanz, Joaquín; Kohn, Jaden R.; Voyles, Tawni; Piqué-Regi, Roger; Wilson, Mark; Barreiro, Luis B.; Tung, Jenny

doi:10.1101/365049

Cited by 11 publications

(16 citation statements)

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“…Thus, while the gene expression signature of social stress may be somewhat conserved across different types of social adversity, and potentially across species, it does not appear to be highly conserved across pathogen environments. Our findings are consistent with previous reports that social status interacts with LPS and glucocorticoid exposure (18,31), and that genetic effects on gene expression can also be altered by local cellular conditions (i.e., gene-environment interactions, e.g., (51)(52)(53)(54)). However, while prior work has primarily shown environment or genotype-dependent differences in the presence or magnitude of effects, here we observed a more striking pattern: directional shifts in the effects of social status, specifically for genes involved in the antiviral response.…”

Section: Discussionsupporting

confidence: 93%

“…For example, genes that are more highly expressed in low status female rhesus macaques are enriched near accessible binding sites for the transcription factor complex nuclear factor kappa-B (NF-κB), a master regulator of inflammation. In contrast, genes that are more highly expressed in high status females fall near accessible binding sites for interferon regulatory factors, which coordinate type I IFN-mediated responses (18,31).…”

Section: Introductionmentioning

confidence: 99%

“…However, exposure to immune stimulants can radically change the transcriptional landscape of immune cells, and social environmental effects on gene expression have been shown to specifically depend on the cellular environment. For example, in rhesus macaque females, social status has more pronounced effects on gene expression after exposure to LPS, but weaker effects on gene expression after exposure to glucocorticoids (18,31). Because no study to date has evaluated the effects of social adversity on gene expression after both bacterial and viral challenge, it is therefore unclear whether chronic social stress in fact attenuates the gene regulatory response to virus, consistent with a trade-offs model.…”

Section: Introductionmentioning

confidence: 99%

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

Sanz

Maurizio²,

Snyder‐Mackler

et al. 2019

Preprint

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Social experiences are 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-κBdependent 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.

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Section: Discussionsupporting

confidence: 93%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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

Sanz

Maurizio²,

Snyder‐Mackler

et al. 2019

Preprint

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“…An increasingly large body of research shows that social status is reflected in patterns of gene regulation (10, 11, 14, 46). Our results reinforce this observation by revealing, for the first time, a strong link between dominance rank and gene expression in a natural mammal population.…”

Section: Discussionmentioning

confidence: 99%

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

Lea

Akinyi

Nyakundi

et al. 2018

Preprint

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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 >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.

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“…This difference is meaningful because this indicates that social status within primate groups is dependent on group membership, which may change and consequently change social status (i.e., Snyder-Mackler et al, 2016;Tung et al, 2012), whereas SES in humans is theoretically independent of group membership and potentially stable. However, given that the group memberships remained stable throughout the study period and that the broad definition of SES in humans refers to the relative access to power with which they can obtain resources (McLoyd, 1998), we and others (e.g., Jarrell et al, 2008;Massart et al, 2017;Snyder-Mackler et al, 2018;Vandeleest et al, 2016) argue that the social construct of status in nonhuman primates is still a good translational model for humans.…”

Section: Research Highlightsmentioning

confidence: 99%

Interindividual differences in neonatal sociality and emotionality predict juvenile social status in rhesus monkeys

Wooddell¹,

Simpson

Murphy

et al. 2018

Developmental Science

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In humans, socioeconomic status (SES) has profound outcomes on socio-emotional development and health. However, while much is known about the consequences of SES, little research has examined the predictors of SES due to the longitudinal nature of such studies. We sought to explore whether interindividual differences in neonatal sociality, temperament, and early social experiences predicted juvenile social status in rhesus monkeys (Macaca mulatta), as a proxy for SES in humans. We performed neonatal imitation tests in infants' first week of life and emotional reactivity assessments at 2 and 4 weeks of age. We examined whether these traits, as well as the rearing environment in the first 8 months of life (with the mother or with same-aged peers only) and maternal social status predicted juvenile (2-3 years old) social status following the formation of peer social groups at 8 months. We found that infants who exhibited higher rates of neonatal imitation and newborn emotional reactivity achieved higher social status as juveniles, as did infants who were reared with their mothers, compared to infants reared with peers. Maternal social status was only associated with juvenile status for infant dyads reared in the same maternal group, indicating that relative social relationships were transferred through social experience. These results suggest that neonatal imitation and emotional reactivity may reflect ingrained predispositions toward sociality that predict later outcomes, and that nonnormative social experiences can alter socio-developmental trajectories. Our results indicate that neonatal characteristics and early social experiences predict later social outcomes in adolescence, including gradients of social stratification.

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

Cited by 11 publications

References 104 publications

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

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

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

Interindividual differences in neonatal sociality and emotionality predict juvenile social status in rhesus monkeys

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