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Journal Article•DOI•

Environmental programming of stress responses through DNA methylation: life at the interface between a dynamic environment and a fixed genome.

Michael J. Meaney1, Moshe Szyf•
McGill University1
01 Jan 2005-Dialogues in Clinical Neuroscience (Les Laboratoires Servier)-Vol. 7, Iss: 2, pp 103-123
TL;DR: It is demonstrated that the structural modifications of the DNA can be established through environmental programming and that, in spite of the inherent stability of this epigenomic marker, it is dynamic and potentially reversible.
Abstract: Early experience permanently alters behavior and physiology. These effects are, in part, mediated by sustained alterations in gene expression in selected brain regions. The critical question concerns the mechanism of these environmental “programming” effects. We examine this issue with an animal model that studies the consequences of variations in mother-infant interactions on the development of individual differences in behavioral and endocrine responses to stress in adulthood. Increased levels of pup licking/grooming by rat mothers in the first week of life alter DNA structure at a glucocorticoid receptor gene promoter in the hippocampus of the offspring. Differences in the DNA methylation pattern between the offspring of high- and low-lickinglgrooming mothers emerge over the first week of life; they are reversed with cross-fostering; they persist into adulthood; and they are associated with altered histone acetylation and transcription factor (nerve growth factor-induced clone A [NGFIA]) binding to the glucocorticoid receptor promoter. DNA methylation alters glucocorticoid receptor expression through modifications of chromatin structure. Pharmacological reversal of the effects on chromatin structure completely eliminates the effects of maternal care on glucocorticoid receptor expression and hypothalamic-pituitary-adrenal (HPA) responses to stress, thus suggesting a causal relation between the maternally induced, epigenetic modification of the glucocorticoid receptor gene and the effects on stress responses in the offspring. These findings demonstrate that the structural modifications of the DNA can be established through environmental programming and that, in spite of the inherent stability of this epigenomic marker, it is dynamic and potentially reversible.
Citations
More filters
疟原虫var基因转换速率变化导致抗原变异[英]／Paul H, Robert P, Christodoulou Z, et al//Proc Natl Acad Sci U S A

[...]

宁北芳, 朱淮民
28 Jul 2005
TL;DR: PfPMP1）与感染红细胞、树突状组胞以及胎盘的单个或多个受体作用，在黏附及免疫逃避中起关键的作�ly.
Abstract: 抗原变异可使得多种致病微生物易于逃避宿主免疫应答。表达在感染红细胞表面的恶性疟原虫红细胞表面蛋白1（PfPMP1）与感染红细胞、内皮细胞、树突状细胞以及胎盘的单个或多个受体作用，在黏附及免疫逃避中起关键的作用。每个单倍体基因组var基因家族编码约60种成员，通过启动转录不同的var基因变异体为抗原变异提供了分子基础。

18,940 citations

Journal Article•DOI•
The Lifelong Effects of Early Childhood Adversity and Toxic Stress

[...]

Jack P. Shonkoff, Andrew S. Garner
01 Jan 2012-Pediatrics
TL;DR: An ecobiodevelopmental framework is presented that suggests that many adult diseases should be viewed as developmental disorders that begin early in life and that persistent health disparities associated with poverty, discrimination, or maltreatment could be reduced by the alleviation of toxic stress in childhood.
Abstract: in fields of inquiry as diverse as neuroscience, molecular biology, genomics, developmental psychology, epidemiology, sociology, and economics are catalyzing an important paradigm shift in our un- derstanding of health and disease across the lifespan. This converging, multidisciplinary science of human development has profound impli- cations for our ability to enhance the life prospects of children and to strengthen the social and economic fabric of society. Drawing on these multiple streams of investigation, this report presents an ecobiodeve- lopmental framework that illustrates how early experiences and envi- ronmental influences can leave a lasting signature on the genetic predispositions that affect emerging brain architecture and long-term health. The report also examines extensive evidence of the disruptive impacts of toxic stress, offering intriguing insights into causal mech- anisms that link early adversity to later impairments in learning, be- havior, and both physical and mental well-being. The implications of this framework for the practice of medicine, in general, and pediatrics, specifically, are potentially transformational. They suggest that many adultdiseasesshouldbeviewedasdevelopmentaldisordersthatbegin early in life and that persistent health disparities associated with pov- erty, discrimination, or maltreatment could be reduced by the allevi- ation of toxic stress in childhood. An ecobiodevelopmental framework alsounderscoresthe needfornewthinking aboutthe focus andbound- aries of pediatric practice. It calls for pediatricians to serve as both front-line guardians of healthy child development and strategically po- sitioned, community leaders to inform new science-based strategies that build strong foundations for educational achievement, economic productivity, responsible citizenship, and lifelong health. Pediatrics

3,248 citations

Journal Article•DOI•
If it goes up, must it come down? Chronic stress and the hypothalamic-pituitary-adrenocortical axis in humans.

[...]

Gregory E. Miller1, Edith Chen1, Eric S. Zhou1•
University of British Columbia1
01 Jan 2007-Psychological Bulletin
TL;DR: A meta-analysis showed that much of the variability in HPA activity is attributable to stressor and person features, as hormonal activity is elevated at stressor onset but reduces as time passes.
Abstract: The notion that chronic stress fosters disease by activating the hypothalamic-pituitary-adrenocortical (HPA) axis is featured prominently in many theories. The research linking chronic stress and HPA function is contradictory, however, with some studies reporting increased activation, and others reporting the opposite. This meta-analysis showed that much of the variability is attributable to stressor and person features. Timing is an especially critical element, as hormonal activity is elevated at stressor onset but reduces as time passes. Stressors that threaten physical integrity, involve trauma, and are uncontrollable elicit a high, flat diurnal profile of cortisol secretion. Finally, HPA activity is shaped by a person's response to the situation; it increases with subjective distress but is lower in persons with posttraumatic stress disorder.

2,196 citations

Cites background from "Environmental programming of stress..."

  • ...The importance of considering development has been highlighted in studies of rodents, in which early-life experiences have been shown to program HPA axis functions at the genomic level, such that they remain altered all the way into adulthood (Liu et al., 1997; Meaney & Szyf, 2005)....

    [...]

Journal Article•DOI•
The neurobiology of stress and development.

[...]

Megan R. Gunnar, Karina Quevedo1•
University of Minnesota1
01 Jan 2007-Annual Review of Psychology
TL;DR: The anatomy and physiology of stress responding, the relevant animal literature, and the importance of individual differences as a lens through which to approach questions about stress experiences during development and child outcomes are reviewed.
Abstract: Stress is a part of every life to varying degrees, but individuals differ in their stress vulnerability. Stress is usefully viewed from a biological perspective; accordingly, it involves activation of neurobiological systems that preserve viability through change or allostasis. Although they are necessary for survival, frequent neurobiological stress responses increase the risk of physical and mental health problems, perhaps particularly when experienced during periods of rapid brain development. Recently, advances in noninvasive measurement techniques have resulted in a burgeoning of human developmental stress research. Here we review the anatomy and physiology of stress responding, discuss the relevant animal literature, and briefly outline what is currently known about the psychobiology of stress in human development, the critical role of social regulation of stress neurobiology, and the importance of individual differences as a lens through which to approach questions about stress experiences during development and child outcomes.

1,661 citations

Cites background from "Environmental programming of stress..."

  • ...F or p er so na l u se o nl y. ANRV296-PS58-07 ARI 17 November 2006 1:24 in rat mothering impact the developing neurobiology of stress (see review by Meaney & Szyf 2005)....

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  • ...…responses of the HPA system, high levels of hippocampal GRs mean efficient control of HPA stress response, whereas low levels mean poor or sluggish regulation, more prolonged stress reactions, and vulnerability to allostatic load over the animal’s lifetime (Meaney & Szyf 2005, Weaver et al. 2001)....

    [...]

Journal Article•DOI•
The link between childhood trauma and depression: insights from HPA axis studies in humans.

[...]

Christine Heim1, D. Jeffrey Newport1, Tanja Mletzko1, Andrew H. Miller1, Charles B. Nemeroff1 •
Emory University1
01 Jul 2008-Psychoneuroendocrinology
TL;DR: Results from a series of clinical studies suggesting that childhood trauma in humans is associated with sensitization of the neuroendocrine stress response, glucocorticoid resistance, increased central corticotropin-releasing factor activity, immune activation, and reduced hippocampal volume are summarized, indicating the existence of biologically distinguishable subtypes of depression as a function of childhood trauma.

1,440 citations

Cites background or result from "Environmental programming of stress..."

  • ...Upon further stress, such women may then repeatedly hypersecrete CRF, eventually resulting in pituitary CRF receptor downregulation and symptoms of depression through CRF effects in extra-hypothalamic circuits....

    [...]

  • ...…link between childhood trauma and depression: Insights from HPA axis studies in humans Christine Heim , D. Jeffrey Newport, Tanja Mletzko, Andrew H. Miller, Charles B. Nemeroff Department of Psychiatry and Behavioral Sciences, Emory University School of Medicine, 101 Woodruff Circle, WMRB, Suite...

    [...]

  • ...These results concur with reports that early adversity in rodents induces reduced expression of central glucocorticoid receptors (GR) at the epigenomic level, by inducing DNA methylation at a promoter site of the GR gene (Weaver et al., 2004; Meaney and Szyf, 2005)....

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  • ...Findings from animal models provide firm evidence for multiple changes in these circuits that occur as a consequence of early-life stress (e.g., Ladd et al., 2000; Sánchez et al., 2001; Meaney and Szyf, 2005)....

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  • ...These changes converge in increased endocrine and autonomic reactivity to stress, anxiety-like behavior, anhedonia, cognitive impairment, pain sensitivity, and altered sleep (e.g., reviewed in Ladd et al., 2000; Sánchez et al., 2001; Plotsky et al., 2001; Meaney and Szyf, 2005)....

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References
More filters
疟原虫var基因转换速率变化导致抗原变异[英]／Paul H, Robert P, Christodoulou Z, et al//Proc Natl Acad Sci U S A

[...]

宁北芳, 朱淮民
28 Jul 2005
TL;DR: PfPMP1）与感染红细胞、树突状组胞以及胎盘的单个或多个受体作用，在黏附及免疫逃避中起关键的作�ly.
Abstract: 抗原变异可使得多种致病微生物易于逃避宿主免疫应答。表达在感染红细胞表面的恶性疟原虫红细胞表面蛋白1（PfPMP1）与感染红细胞、内皮细胞、树突状细胞以及胎盘的单个或多个受体作用，在黏附及免疫逃避中起关键的作用。每个单倍体基因组var基因家族编码约60种成员，通过启动转录不同的var基因变异体为抗原变异提供了分子基础。

18,940 citations

Journal Article•DOI•
Relationship of childhood abuse and household dysfunction to many of the leading causes of death in adults. The Adverse Childhood Experiences (ACE) Study

[...]

Vincent J. Felitti1, Robert F. Anda2, Dale F. Nordenberg3, David F. Williamson2, Alison M. Spitz2, Valerie J. Edwards2, Mary P. Koss4, James S. Marks2 •
Kaiser Permanente1, Centers for Disease Control and Prevention2, Emory University3, University of Arizona4
01 May 1998-American Journal of Preventive Medicine
TL;DR: For example, this article found a strong relationship between the breadth of exposure to abuse or household dysfunction during childhood and multiple risk factors for several of the leading causes of death in adults.

12,712 citations

Journal Article•DOI•
How do glucocorticoids influence stress responses? Integrating permissive, suppressive, stimulatory, and preparative actions.

[...]

Robert M. Sapolsky1, L. Michael Romero2, Allan Munck3•
Stanford University1, Tufts University2, Dartmouth College3
01 Feb 2000-Endocrine Reviews
TL;DR: This review considers recent findings regarding GC action and generates criteria for determining whether a particular GC action permits, stimulates, or suppresses an ongoing stress-response or, as an additional category, is preparative for a subsequent stressor.
Abstract: The secretion of glucocorticoids (GCs) is a classic endocrine response to stress. Despite that, it remains controversial as to what purpose GCs serve at such times. One view, stretching back to the time of Hans Selye, posits that GCs help mediate the ongoing or pending stress response, either via basal levels of GCs permitting other facets of the stress response to emerge efficaciously, and/or by stress levels of GCs actively stimulating the stress response. In contrast, a revisionist viewpoint posits that GCs suppress the stress response, preventing it from being pathologically overactivated. In this review, we consider recent findings regarding GC action and, based on them, generate criteria for determining whether a particular GC action permits, stimulates, or suppresses an ongoing stressresponse or, as an additional category, is preparative for a subsequent stressor. We apply these GC actions to the realms of cardiovascular function, fluid volume and hemorrhage, immunity and inflammation, metabolism, neurobiology, and reproductive physiology. We find that GC actions fall into markedly different categories, depending on the physiological endpoint in question, with evidence for mediating effects in some cases, and suppressive or preparative in others. We then attempt to assimilate these heterogeneous GC actions into a physiological whole. (Endocrine Reviews 21: 55‐ 89, 2000)

6,707 citations

"Environmental programming of stress..." refers background in this paper

  • ...CRF synthesis and release are inhibited through a glucocorticoid negative-feedback system mediated by both mineralocorticoid and glucocorticoid receptors (GRs) in a number of brain regions including, and perhaps especially in, the hippocampus.(46,47) CRF neurons in the amygdala project directly to the locus ceruleus and increase the firing rate of locus ceruleus neurons, resulting in increased noradrenaline release in the vast terminal fields of this ascending noradrenergic system....

    [...]

Journal Article•DOI•
Protective and Damaging Effects of Stress Mediators

[...]

Bruce S. McEwen1•
Rockefeller University1
15 Jan 1998-The New England Journal of Medicine
TL;DR: The long-term effect of the physiologic response to stress is reviewed, which I refer to as allostatic load, which is the ability to achieve stability through change.
Abstract: Over 60 years ago, Selye1 recognized the paradox that the physiologic systems activated by stress can not only protect and restore but also damage the body. What links these seemingly contradictory roles? How does stress influence the pathogenesis of disease, and what accounts for the variation in vulnerability to stress-related diseases among people with similar life experiences? How can stress-induced damage be quantified? These and many other questions still challenge investigators. This article reviews the long-term effect of the physiologic response to stress, which I refer to as allostatic load.2 Allostasis — the ability to achieve stability through change3 — . . .

5,932 citations

Journal Article•DOI•
Transcriptional repression by the methyl-CpG-binding protein MeCP2 involves a histone deacetylase complex

[...]

Xinsheng Nan1, Huck-Hui Ng1, Colin A. Johnson2, Carol D. Laherty3, Bryan M. Turner2, Robert N. Eisenman3, Adrian Bird1 •
University of Edinburgh1, University of Birmingham2, Fred Hutchinson Cancer Research Center3
28 May 1998-Nature
TL;DR: The data suggest that two global mechanisms of gene regulation, DNA methylation and histone deacetylation, can be linked by MeCP2, an abundant nuclear protein that is essential for mouse embryogenesis.
Abstract: Cytosine residues in the sequence 5'CpG (cytosine-guanine) are often postsynthetically methylated in animal genomes. CpG methylation is involved in long-term silencing of certain genes during mammalian development and in repression of viral genomes. The methyl-CpG-binding proteins MeCP1 and MeCP2 interact specifically with methylated DNA and mediate transcriptional repression. Here we study the mechanism of repression by MeCP2, an abundant nuclear protein that is essential for mouse embryogenesis. MeCP2 binds tightly to chromosomes in a methylation-dependent manner. It contains a transcriptional-repression domain (TRD) that can function at a distance in vitro and in vivo. We show that a region of MeCP2 that localizes with the TRD associates with a corepressor complex containing the transcriptional repressor mSin3A and histone deacetylases. Transcriptional repression in vivo is relieved by the deacetylase inhibitor trichostatin A, indicating that deacetylation of histones (and/or of other proteins) is an essential component of this repression mechanism. The data suggest that two global mechanisms of gene regulation, DNA methylation and histone deacetylation, can be linked by MeCP2.

3,396 citations

"Environmental programming of stress..." refers background in this paper

  • ...Methylated DNA attracts methylated DNA binding proteins, which recruit a cluster of proteins referred to as repressor complexes, which include histone deacetylases that result in inactive chromatin and the silencing of gene expression.(105,106) The model positioning DNA methylation as driving chromatin inactivation is pervasive....

    [...]

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