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. Author manuscript; available in PMC: 2014 Oct 1.
Published in final edited form as: Int J Dev Neurosci. 2013 Mar 14;31(6):448–451. doi: 10.1016/j.ijdevneu.2013.03.004

Developmental Regulation of Neuronal Genes by DNA Methylation: Environmental Influences

Melinda E Wilson 1,*, Tomoko Sengoku 1
PMCID: PMC3703480  NIHMSID: NIHMS460180  PMID: 23501000

Abstract

Steroid hormones have wide-ranging organizational, activational and protective actions in the brain. In particular, the organizational effects of early exposure to 17β-estradiol (E2) and glucocorticoids are essential for long-lasting behavioral and cognitive functions. Both steroid hormones mediate many of their actions through intracellular receptors that act as transcription factors. In the rodent cerebral cortex, estrogen receptor mRNA and protein expression are high early in postnatal life and declines dramatically as the animal approaches puberty. An understanding of the molecular mechanisms driving this developmental regulation of gene expression is critical for understanding the complex events that determine lasting brain physiology and prime the plasticity of neurons. Gene expression can be suppressed by the epigenetic modification of the promoter regions by DNA methylation that results in gene silencing. Indeed, the decrease in ERα mRNA expression in the cortex during development is accompanied by an increase in promoter methylation. Numerous environmental stimuli can alter the DNA methylation that occurs for ERα, glucocorticoid receptors, as well as many other critical genes involved in neuronal development. For example, maternal behavior towards pups can alter epigenetic regulation of ERα mRNA expression. Additionally perinatal stress and exposure to environmental estrogens can also have lasting effects on gene expression by modifying DNA methylation of these important genes. Taken together, there appears to be a critical window during development where, outside factors that alter epigenetic programming can have lasting effects on neuronal gene expression.

Introduction

Steroid hormones play a crucial role in coordinating many neuroendocrine events that control sexual development, sexual behavior and reproduction. 17β-estradiol is the primary biologically active form of estrogen and in rodents, it is critical for sexual differentiation of the brain (see review by (McCarthy 2008)). For example, estradiol organizes neural circuits and regulates apoptosis of neurons leading to long-term differences in the male and female brain (Toran-Allerand 1976; Anderson, Fleming et al. 1986; Rhees, Shryne et al. 1990). Many of the physiological effects of estrogen are mediated primarily by two intracellular receptors, ERα and ERβ (Green, Walter et al. 1986; Koike, Sakai et al. 1987; White, Lees et al. 1987; Kuiper, Enmark et al. 1996; Mosselman, Polman et al. 1996). Both ERα and ERβ are expressed in neurons and glia (Donahue, Stopa et al. 2000; Chaban, Lakhter et al. 2004), and both are expressed throughout the brain with distinct patterns in different brain regions and with differing levels of expression during development (Shughrue, Lane et al. 1997; Osterlund, Grandien et al. 2000; Osterlund, Gustafsson et al. 2000; Gonzalez, Cabrera-Socorro et al. 2007; Prewitt 2007). Estrogen action in the cortex may play a role in regulating learning and memory (McEwen and Alves 1999; Simpkins and Singh 2008) and contribute to sex differences observed therein.

Glucocorticoids also play an important role in establishing the neonatal brain’s life-long response to stress. In particular glucocorticoid receptor (GR) expression in the hippocampus and amygdala are crucial for regulating stress and anxiety (Herman, McKlveen et al. 2012). Thus, an understanding of the regulation of steroid hormone receptors in non-reproductive brain regions such as the cortex and hippocampus is a critical, yet understudied area. In this manuscript we will review some of what is known about the mechanisms of normal developmental regulation of ERα mRNA as well as factors that can disrupt this regulation of ERα and GR.

The regulation of gene expression by epigenetic modification is an emerging mechanism for controlling neuronal gene expression (for review see (Takizawa and Meshorer 2008) and (Mehler 2008). Epigenetic modification of chromatin involves changes to DNA bases and the associated proteins in the absence of changes in the DNA sequence. Epigenetic modifications can include histone acetylation, histone methylation and DNA methylation (Wolffe 1998). All of these modifications can contribute to lasting changes in gene expression and can be associated with either gene repression or gene expression. In this review we will primarily focus on the gene suppression by DNA methylation. The first step in DNA methylation results in the enzymatic transfer of a methyl group to the 5′-position of the pyrimidine ring of a cytosine residue followed by a guanine (CpG dinucleotides). DNA methyltransferase 3A (DNMT3A) initiates this modification and it is maintained by DNMT1 (Klose and Bird 2006). CpG residues are often found upstream or downstream of the transcriptional start site. These methylated cytosines direct DNA methyl binding proteins such as methyl binding domainproteins 1, 2, 3, 4 and MeCP2 (Nan, Ng et al. 1998; Ng, Zhang et al. 1999; Ng, Jeppesen et al. 2000) which can induce histone deacetylases and suppress transcription. Epigenetic modification of chromatin in neurons has, indeed, been shown to play an important role in regulating gene expression during neuronal development and in learning and memory (Levenson and Sweatt 2005; Kiefer 2007; Day and Sweatt 2011; Guo, Ma et al. 2011). MeCP2 gene mutations are also the cause of some cases of Rett syndrome, a progressive neurological developmental disorder that appears during early childhood when sensory experience is driving the synaptic reorganization required for creating mature circuits in the brain (Zoghbi 2003) (Guy, Hendrich et al. 2001). Additionally, MeCP2 is differentially expressed in the hypothalamus during a critical time in sexual differentiation of the brain (Kurian, Bychowski et al. 2008). Furthermore, DNMT3 expression has also been shown to be dynamically regulated in the developing brain as well as in the adult cortex (Feng, Chang et al. 2005; Siegmund, Connor et al. 2007; Westberry, Trout et al. 2010). These correlative changes suggest that DNA methylation may be involved in determining the expression pattern of neuronal genes during neuronal development.

Developmental regulation of estrogen receptor-alpha mRNA

One example of a neuronal gene that is developmentally regulated during brain development is the estrogen receptor alpha (ERα) gene. Both ERα protein and mRNA levels change dramatically during postnatal brain development (Simerly, Chang et al. 1990; Toran-Allerand, Miranda et al. 1992; Shughrue, Lane et al. 1997). High levels of estradiol binding in non-hypothalamic regions such as the cortex and hippocampus are apparent during the first two weeks of life (Pfaff and Keiner 1973; Sheridan 1979; Shughrue, Stumpf et al. 1990). This expression, however, declines as animals approach puberty. In rats and mice, ERα mRNA expression was shown to correlate with the changes in estrogen binding in the hippocampus and cortex (O’Keefe, Li et al. 1995; Prewitt 2007). Furthermore, when either fetal rat hippocampal or cortical tissue was transplanted to the brain of a neonatal animal, the developmental profile of ERα mRNA expression in the transplants continued with the profile of the age of the donor (O’Keefe, Pedersen et al. 1993), suggesting that the control of ERα gene expression is programmed in the developing tissue itself and does not rely on cues from the surrounding tissue.

To investigate such additional potential mechanisms regulating this decline in ERα mRNA expression across early postnatal development, we examined the methylation status of the ERα promoter. We have observed that several of the promoters of the mouse ERα gene become progressively methylated beginning at postnatal day 10 (Westberry, Trout et al. 2010). This age corresponds with the beginning of the decline in ERα mRNA expression in the cortex. Furthermore, chromatin immunoprecipitation assays determined that the methyl-DNA binding protein, MeCP2, is associated with this promoter at the same time it becomes methylated. These observations suggest that methylation does play a role in the suppression of ERα mRNA in the developing brain and that the ERα promoter is a target of MeCP2 activity. Additionally we examined the expression pattern of the de novo DNMT, DNMT3A, in the isocortex, prefrontal cortex and hippocampus. A gradual increase with age was observed in DNMT3A mRNA expression (Westberry, Trout et al. 2010).

ERα is also developmentally regulated by epigenetic modification in other areas of the brain normally associated with reproduction, such as the preoptic area of the hypothalamus. Auger and colleagues have shown that ERα mRNA expression is higher in females as compared to males and there is a corresponding decrease in methylation of the ERα promoter (Kurian, Olesen et al. 2010). Furthermore, they and others have demonstrated a developmental sex difference in DNMT expression in the hypothalamus, suggesting not only are epigenetic mechanisms regulation important in development, but in generating sex differences gene expression as well (McCarthy, Auger et al. 2009).

Environmental influences on epigenetic regulation of steroid hormone receptor gene expression

Stress

The normal developmental process of gene expression that is intrinsically controlled is susceptible to disruption by many outside influences. Maternal care during the first two weeks of life in rodent provides lasting influence during this critical window in brain development. Meaney and colleagues were the first to demonstrate that maternal behavior could alter gene expression by modifying chromatin (Weaver, Cervoni et al. 2004). They observed that there were two types of maternal behaviors: high-licking and low-licking grooming that could alter gene expression and behavior in their offspring (Liu, Diorio et al. 1997; Champagne, Francis et al. 2003). Pups with high-licking mothers tended to have a lower stress response as adults, along with increased glucocorticoid receptor (GR) expression in the hippocampus. These changes in gene expression were also shown to be accompanied by epigenetic modifications in the promoter for the glucocorticoid receptor gene. In the high-lick offspring where GR mRNA expression was increased, the promoter was less methylated when compared to low-lick offspring (Weaver, Cervoni et al. 2004). Additionally, associated with maternal behavior towards offspring, prenatal stressors have also been shown to alter DNA methylation patterns and neuronal gene expression leading to lasting effects into adulthood (Goel and Bale 2007). Bale and colleagues have demonstrated that varied stress in utero could lead to changes in corticotrophin releasing factor and GR expression associated with alterations in promoter methylation in the hypothalamus and amygdala (Mueller and Bale 2008). These changes were correlated with depressed behavioral response to several stressors in male offspring as adults.

In addition to the GR promoter, the ERα promoter was shown to also be susceptible to changes in DNA methylation caused by maternal grooming (Champagne, Weaver et al. 2006). Female offspring from high-licking mothers had lower levels of promoter methylation of ERα in the hypothalamus corresponding with the increased expression of ERα mRNA. These changes are maintained in adulthood and associated with similar grooming activities in the females when they care for pups (Francis, Diorio et al. 1999). Additionally, altered ERα expression and methylation is also associated with altered lordosis behaviors where low-lick females are more responsive to males (Cameron, Shahrokh et al. 2008). Taken together, either prenatal or postnatal exposure to stress can have lasting effects on gene expression and behaviors in the offspring that appear to be mediated by DNA methylation.

Endocrine disruptors

Exposure to environmental toxins can have wide ranging teratogenic effects in developing animals. In particular, estrogenic compounds from plastics found in the environment, such as bisphenol A (BPA), can have numerous negative effects on multiple tissues depending on the dose, length, and timing of exposure (Rubin 2011). While studies in humans have been mostly correlative, direct effects of BPA exposure have been shown to have a variety of adverse effects in rodents. In particular BPA exposure in the developing fetus or neonate can alter the timing of puberty (Howdeshell, Hotchkiss et al. 1999; Honma, Suzuki et al. 2002), alter estrous cycles (Rubin, Murray et al. 2001; Monje, Varayoud et al. 2010), cause prostate neoplasia (Prins, Birch et al. 2007), alter mammary gland development (Markey, Luque et al. 2001; Vandenberg, Maffini et al. 2008) and alter aggressive and cognitive behaviors (Kawai, Nozaki et al. 2003; Tian, Hwan Kim et al. 2011). BPA exposure of female rats during the first week of life results in lower ERα mRNA levels in the medial preoptic area and ventromedial nucleus of the hypothalamus (Monje, Varayoud et al. 2007). This suppression is also associated with a disruption in gonadotropin releasing hormone production, potentially leading to reproductive deficits (Monje, Varayoud et al. 2010). Furthermore, BPA exposure in utero results in alterations in global methylation patterns of genes expressed in the forebrains of exposed mice which could potentially lead to far-reaching negative consequences in behavior and cognition (Yaoi, Itoh et al. 2008). These results again demonstrate that there is a critical window of coordinated neuronal gene expression that is susceptible to environmental factors that alter DNA methylation. These changes can potentially lead to lasting changes in gene expression and behavior in adulthood.

Summary

Coordinated regulation of the steroid hormone receptor genes is critical for mediating the response to hormones in an age, gender, and brain region-specific manner. In this review we have touched upon several physiological and environmental influences that can alter the expression of the estrogen receptor and glucocorticoid receptor genes in the cortex, hippocampus and hypothalamus by DNA methylation. A deeper understanding of these mechanisms will ultimately lead to our understanding of the molecular mechanisms underlying how gene expression in the brain develops and ultimately, how neuronal genes respond to neuronal insults associated with injury, neurodegeneration or normal aging.

Highlights.

  • Neuronal gene expression is developmentally regulated in an intrinsic fashion.

  • Estrogen receptor alpha expression is shut down by DNA methylation in the cortex.

  • Environmental factors can influence the epigenetic machinery in neonatal rodents.

Acknowledgments

This work cited from our laboratory was supported by the National Science Foundation (NSF IOS0919944 and NSF IOS1121129) (MEW) and COBRE grant P20 RR15592 from the National Center for Research Resources (NCRR). All opinions, findings and conclusions expressed in this material are those of the authors and not those necessarily of NSF or NCRR.

Footnotes

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