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      Environmental programming of stress responses through DNA methylation: life at the interface between a dynamic environment and a fixed genome Translated title: Programación ambiental de las respuestas de estrés mediante la metilación del ADN: vida en la interfase entre un ambiente dinámico y un genoma estable Translated title: Programmation environnementale des réponses au stress par méthylation de l'ADN: la vie à l'interface entre un environnement dynamique et un génome fixé

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          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.

          Translated abstract

          Una experiencia precoz altera en forma permanente la conducta y la fisiología. Estos efectos son mediados, en parte, por alteraciones que se sustentan en la expresión génica de regiones cerebrales específicas. La pregunta central se refiere al mecanismo de estos efectos en la "programación" ambiental. En este artículo se examina este tema con un modelo animal que estudia las consecuencias de las variaciones en las interacciones entre la madre y la cría en el desarrollo de diferencias individuales en la respuesta conductual y endocrina al estrés durante la adultez. Un aumento en la conducta de aseo con lamidos a las crías por las ratas madre durante la primera semana de vida altera la estructura del ADN del gen promotor del receptor de glucocorticoides en el hipocampo de las crías. Diferencias en el patrón de metilación del ADN entre las crías de madres con altas y bajas conductas de aseo con lamidos aparecen en la primera semana de vida; éstas pueden revertir mediante la adopción cruzada, pueden persistir a lo largo de la adultez y pueden asociarse con una alteración de la acetilación de histona y de la fijación del factor de transcripción (clon A inducido por el factor de crecimiento neural [NGFIA]) al promotor del receptor de glucocorticoides. La metilación del ADN altera la expresión del receptor de glucocorticoides a través de modificaciones en la estructura de la cromatina. La reversión de los efectos en la estructura de la cromatina producida farmacológicamente elimina completamente los efectos de los cuidados maternos en la expresión del receptor de glucocorticoides y en la respuesta del eje hipotálamo-hipófisis-adrenal (HHA) al estrés, lo que sugiere una relación causal entre la modificación epigenética del gen del receptor de glucocorticoides, inducida por la madre, y los efectos en la respuesta al estrés en las crías. Estos hallazgos demuestran que las modificaciones estructurales del ADN se pueden establecer mediante programación ambiental y que, a pesar de la estabilidad intrínseca de este marcador epigenómico, éste es dinámico y potencial mente reversible.

          Translated abstract

          Les expériences précoces de la vie modifient en permanence le comportement et la physiologie. Ces effets sont en partie, dus à des transformations prolongées de l'expression génique dans des régions cérébrales sélectionnées. La question principale concerne le mécanisme de ces effets «programmants» environnementaux. Nous examinons ce problème sur un modèle animal qui étudie les conséquences des variations des interactions mère-enfant sur le développement des différences individuelles dans les réponses au stress, endocrines et environnementales, à l'âge adulte. Un léchage/toilettage intense de petits de rats par leur mère dans la première semaine de vie modifie la structure de l'ADN au niveau du gène promoteur d'un récepteur glucocorticoïde dans l'hippocampe de la descendance. Les différences de schémas de méthylation de I'ADN entre les descendants de mères fortement ou faiblement lécheuses apparaissent après la première semaine de vie; elles sont réversibles avec l'échange des mères; elles persistent à l'âge adulte et sont associées à une modification de l'acétylation de l'histone et du facteur de transcription (facteur de croissance nerveux induit par clone A [NGFIA]) en liaison avec le promoteur du récepteur glucocorticoïde. La méthylation de I'ADN modifie l'expression du récepteur glucocorticoïde par les changements de structure de la chromatine. L'inversion pharmacologique induite par les changements de structure de la chromatine élimine complètement les effets des soins maternels sur l'expression du récepteur glucocorticoïde et les réponses au stress hypothalamo-adrénalo-pituitaires (HAP), suggérant donc une relation causale entre les modifications épigénétiques du gène du récepteur glucocorticoïde induites par la mère et les effets sur les réponses au stress dans la descendance. Ces résultats démontrent que les changements structuraux de l'ADN peuvent se constituer par l'intermédiaire d'un environnement programmant et que, malgré la stabilité inhérente de ce marqueur épigénomique, elles sont dynamiquement et potentiellement réversibles.

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          Most cited references 118

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          Epigenetic programming by maternal behavior.

          Here we report that increased pup licking and grooming (LG) and arched-back nursing (ABN) by rat mothers altered the offspring epigenome at a glucocorticoid receptor (GR) gene promoter in the hippocampus. Offspring of mothers that showed high levels of LG and ABN were found to have differences in DNA methylation, as compared to offspring of 'low-LG-ABN' mothers. These differences emerged over the first week of life, were reversed with cross-fostering, persisted into adulthood and were associated with altered histone acetylation and transcription factor (NGFI-A) binding to the GR promoter. Central infusion of a histone deacetylase inhibitor removed the group differences in histone acetylation, DNA methylation, NGFI-A binding, GR expression and hypothalamic-pituitary-adrenal (HPA) responses to stress, suggesting a causal relation among epigenomic state, GR expression and the maternal effect on stress responses in the offspring. Thus we show that an epigenomic state of a gene can be established through behavioral programming, and it is potentially reversible.
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            The adaptive significance of maternal effects

             T Mousseau (1998)
            Recently, the adaptive significance of maternal effects has been increasingly recognized. No longer are maternal effects relegated as simple `troublesome sources of environmental resemblance' that confound our ability to estimate accurately the genetic basis of traits of interest. Rather, it has become evident that many maternal effects have been shaped by the action of natural selection to act as a mechanism for adaptive phenotypic response to environmental heterogeneity. Consequently, maternal experience is translated into variation in offspring fitness.
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              Methylated DNA and MeCP2 recruit histone deacetylase to repress transcription.

              CpG methylation in vertebrates correlates with alterations in chromatin structure and gene silencing. Differences in DNA-methylation status are associated with imprinting phenomena and carcinogenesis. In Xenopus laevis oocytes, DNA methylation dominantly silences transcription through the assembly of a repressive nucleosomal array. Methylated DNA assembled into chromatin binds the transcriptional repressor MeCP2 which cofractionates with Sin3 and histone deacetylase. Silencing conferred by MeCP2 and methylated DNA can be relieved by inhibition of histone deacetylase, facilitating the remodelling of chromatin and transcriptional activation. These results establish a direct causal relationship between DNA methylation-dependent transcriptional silencing and the modification of chromatin.
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                Author and article information

                Contributors
                McGill Program for the Study of Behavior, Genes and Environment, Department of Pharmacology, McGill University; Douglas Hospital Research Centre, Montreal, Canada
                Journal
                Dialogues Clin Neurosci
                Dialogues Clin Neurosci
                Dialogues in Clinical Neuroscience
                Les Laboratoires Servier (France )
                1294-8322
                1958-5969
                June 2005
                June 2005
                : 7
                : 2
                : 103-123
                Affiliations
                McGill Program for the Study of Behavior, Genes and Environment, Department of Pharmacology, McGill University; Douglas Hospital Research Centre, Montreal, Canada
                Author notes
                Article
                3181727
                16262207
                Copyright: © 2005 LLS

                This is an open-access article distributed under the terms of the Creative Commons Attribution License ( http://creativecommons.org/licenses/by-nc-nd/3.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

                Categories
                Basic Research

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