Epigenetic Mechanisms Matter in Child Development

Vortrag von Marinus H. van IJzendoorn, Universiteit Leiden*

Prof. Dr. Dr. h.c. Marinus H. van IJzendoornProf. Dr. Dr. h.c. Marinus H. van IJzendoorn

How is it possible that one twin of a monozygotic twin pair develops cancer or depression and the other twin remains free of physical or mental illness? The answer is simple: If identical twins have spent large part of their adult lives exposed to different environments, they are not identical anymore. Their genome undergoes epigenetic (Greek epi = »above« the genome) modifications that affect gene expression without actually changing the sequence of the DNA letters. Epigenetics can be defined as the study of biochemical modifications of the DNA influencing gene expression without altering the structural base-pair sequence itself. The epigenome is not a stable entity but, instead, dynamically interacts with the environment. Although changes in structural DNA sequences (mutations) occur rarely during the life course, epigenetic changes resulting in permanent alterations in gene expression, including silencing of genes, occur more frequently than was ever imagined.

Here, we argue that child development defined as the dynamic interplay between the environment and the individual child is mediated by a series of epigenetic modifications of specific genes resulting in stable and persistent changes in physiology, cognition, emotion, and behavior. Methylation and other epigenetic changes constitute the molecular mechanism by which the environment affects the physiology and behavior of the developing child and development becomes literally embodied in environmentally induced signatures on the epigenome. 

Genetics, epigenetics, and methylation

The double helix of DNA is a specific, meaningful sequence in gene coding regions that contains instructions for the production of specific proteins (Ebstein, Salomon, Chew, Zhong, & Knafo, 2010). It is the structural part of the genome, which is relatively stable across the individual’s lifetime and, through inheritance, across generations. Whereas evolutionary adaptations of the structural genome to changing environments would take numerous generations depending on the strength of selection, epigenetic adaptations occur immediately at any point in an organism’s life course. Epigenetic change starting from fertilization onward both accounts for differentiation of tissues and cells and allows a flexible response to environmental challenges and changes throughout the lifespan.

Methylation of DNA is one of the most widely studied epigenetic means of gene silencing (Tamashiro & Moran, 2010). A methyl molecule (CH3) is covalently linked to cytosine (CpG).
CpGs are grouped in clusters called »CpG islands,« and, in mammals, 60 % – 90 % of the CpG islands are methylated (Jeltsch, 2002). When methylation occurs in gene-promoter regions, gene expression is altered. Once CpG islands are methylated, the methylation pattern is faithfully reproduced each time the gene is copied; thus, the effects of methylation are preserved.

Epigenetic changes and methylation in animal models

Impressive examples of environmental influences on DNA methylation can be found in animal studies. For instance, intergenerational transmission of epigenetic changes has been demonstrated in rats: In a set of experimental and cross-fostering studies, Meany, Szyf, and their colleagues showed that rodent maternal behavior toward offspring (licking and grooming and arch-back nursing) resulted in long-term changes in responses of the offspring to stress (Weaver et al. 2004; Zhang & Meaney, 2010). These changes reflected permanently altered methylation patterns affecting the expression of the glucocorticoid receptor gene (Szyf, Waever, Champagne, Diorio, & Meaney, 2005), with consequences for the next generation’s parenting behavior and stress regulation (Champagne, 2008; Meaney & Szyf, 2005). Similarly, it has been shown that lowquality maternal care affects not only the pups’ stress physiology but also their brain morphology, in a way that on the face of it seems disadvantageous (lower neural density) but that actually enhances learning and memory processes under stressful conditions. The early experience of »neglect« thus prepares the individual optimally for the stressful life that is to be expected (Champagne, 2008). It is important to note that methylation is not good or bad in itself – it is an environmentally primed adaptation that may or may not be adaptive to future environments.

A move to a human development

Translating effects of studies on rodents to human beings is attractive, but it should be realized that a pup’s development is not isomorphic with human development and that the all-over experimental round-the-clock control of the animals’ environment is both impossible and unthinkable with humans. However, studies relating early experiences to epigenetic programming in humans are increasing. For instance, Oberlander and his colleagues (Devlin, Brain, Austin, & Oberlander, 2010; Oberlander et al., 2008) showed that prenatal maternal depression affects methylation patterns of the SLC6A4 promoter encoding the transmembrane serotonin transporter and of the GR glucocorticoid receptor gene involved in cortisol stress responses. Thus, prenatal exposure to maternal depression may »program« child development through epigenetic processes.

Further, the idea that methylation may be a biological basis for the impact of adverse experiences on human psychological development (e. g. Yehuda & Bierer, 2009) was further supported by the finding that higher levels of methylation in the 5HTTLPR were associated with increased risk of unresolved responses to loss or other trauma in carriers of the usually protective 5HTTL- PR ll variant (van IJzendoorn, Caspers, Bakermans-Kranenburg, Beach, & Philibert, 2010).

Low early-life socioeconomic status (SES) has also been related to epigenetic changes in human development. In fact, for humans, conditions of chronic poverty may be a close approximation of the constant manipulation of the environment used in animal models (Hackman, Farah, & Meaney, 2010). Unfavorable socioeconomic conditions in early life are related to up-regulation of genes that convey adrenergic signals to leukocytes and down-regulation of genes related to the glucocorticoid receptor. Through this epigenetic mechanism, low early-life socioeconomic status (SES) may lead to increased susceptibility to infectious and cardiovascular diseases, even when later SES, lifestyle practices, and perceived stress are controlled (Miller et al., 2009). 

Toward developmental behavioral epigenetics

Human behavioral epigenetics is an emerging field still in its earliest stage. Only a handful of studies on epigenetics in human behavioral development have been reported thus far, and a myriad of basic measurement issues still have to be addressed, such as the stability of meythlation across time, and the comparability of methylation levels assessed in DNA from various parts of the body. Traditional behavioral and molecular genetics are based on the assumption of an invariable genotype and a largely irrelevant (shared) environment. Monozygotic twins, however, are not identical phenotypically, especially regarding pathological behaviors, and the expression of genes is continuously in flux, presumably reflecting an ever changing internal as well as external environment. Epigenetic studies make clear that the environment penetrates the genome at its core, and influences the expression or non-expression of genes. Gene X Environment interactions have been interpreted as the genetic moderation of environmental influences on child development. From an epigenetics perspective, environmental pressures are hypothesized to regulate levels of methylation along specific genes. Hence, it seems worthwhile to add methylation to the G X E equation to fully appreciate the effects of the environment on child and adult functioning.

The application of epigenetics to the study of child development is a fascinating next step in unravelling the intricate interplay between rearing environment and the child’s genome. Prime among the new questions to be addressed are those concerning intergenerational transmission of epigenetic changes and the reversibility of DNA methylation in children through psychosocial intervention or pharmacological treatment. From an epigenetic perspective, divisions between genes, brain, and behavior are artificial, as the environment becomes embodied in the epigenome. In fact, to a large extent, nature is nurture. And methylation matters if one wants to understand how the early environment leaves its lasting imprint on the child.

* Kurzfassung des Aufsatzes »Methylation Matters in Child Development: Toward Developmental Behavioral Epigenetics«, Marinus H. van IJzendoorn, Marian J. Bakermans-Kranenburg, and Richard P. Ebstein, in: Child Development Perspectives, 5(4), 305 -310, The Society for Research in Child Development. (Kurzfassung erstellt von Anna Neumann, NZFH) 

References:

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Devlin, A.M., Brain, U., Austin, J., & Oberlander, T.F. (2010). Prenatal exposure to maternal depressed mood and the MTHFR C677T variant affect SLC6A4 methyl- ation in infants at birth. PLoS ONE, 5, e12201, 1–8.

Ebstein, R.P., Salomon, I., Chew, S.H., Zhong, S., & Knafo, A. (2010). Genetics of human social behavior. Neuron, 65, 831–844.

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Miller, G.E., Chen, E., Fok, A.K., Walker, H., Lim, A., Nicholls, E.F., et al. (2009). Low early-life social class leaves a biological residue manifested by decreased glucocorticoid and increased proinflammatory signaling. PNAS, 106, 14716–14721.

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