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Epigenetics—New frontiers in neuroendocrinology
Available online at www.sciencedirect.com
Frontiers in Neuroendocrinology Frontiers in Neuroendocrinology 29 (2008) 341–343 www.elsevier.com/locate/yfrne
Editorial
Epigenetics—New frontiers in neuroendocrinology The NIH (National Institutes of Health, US) Roadmap for biomedical research priorities was implemented in 2002, signaling a sea change in one of the largest sponsors of scientific research in the world. The goal was to identify major opportunities and gaps in research that no one group or institute could tackle alone. Five years later, in early 2007, an update to the roadmap identified Epigenetics as one of two subject areas approved for immediate implementation (http://nihroadmap.nih.gov/roadmap15update. asp). The question is, who will do the implementing? Neuroendocrinology is a cross-cutting discipline by definition and therefore uniquely situated to make major advances in our understanding of the complex interplay between genes, the environment, the brain and behavior. The intent of this special issue of Frontiers in Neuroendocrinology is to acquaint the novice with the topic of epigenetics and its terminology (Table 1), highlight the work that is currently being conducted in the field, and prompt more interest and ultimately research on the role of epigenetic variables in neuroendocrine systems. One of the challenges in epigenetics is how to define it beyond its obvious meaning of ‘‘above genetics”. The NIH defines epigenetics as the study of stable genetic modifications that result in changes in gene expression and function without a corresponding alteration in DNA sequence. The epigenome is a catalog of the epigenetic modifications that occur in the genome. David Crews points out in this issue (Crews, 2008), that definitions such as this do not distinguish between epigenetic changes that are independent of the germline, what he terms ContextDependent epigenetic changes, and Germline-Dependent modification or transmission through a single cell bottleneck, the gametes. Examples of both are included in this issue. Crews further distinguishes epigenetics as being Molecular versus Molar as a way of codifying the level of analysis. The meaning of the former is fairly self-evident, referring to the nuts and bolts, or molecular modifications of the genome (but not the DNA sequence). The latter is a term rooted in functional psychology that encompasses the interactions between cells, physiological and neuroendocrine systems, or individuals and how they are adapted to the social and biotic environments. Both concepts are elaborated on in detail in this issue (Crews, 2008).
0091-3022/$ - see front matter Ó 2008 Elsevier Inc. All rights reserved. doi:10.1016/j.yfrne.2008.01.002
An excellent example of Context-Dependent epigenetic changes is presented in the review by Frances Champagne (Champagne, 2008) of her own and others’ seminal work on the impact of maternal behavior on various aspects of neuronal functioning in the offspring. Mothers who groom their offspring with a low frequency produce changes in the methylation of GC residues in the promoter region of the gene coding for the estrogen receptor (ER) for the lifetime of the young. The consequence of the methylation is to block the transcription of the gene, thereby reducing the amount of estrogen receptor in the preoptic area. This in turn has important consequences for oxytocin receptor expression. Oxytocin is a critical affiliative hormone capable of modulating a wide range of behaviors considered central to mental health and well-being. Thus she provides an elegant example of how behavioral experience can alter gene expression in one system, ERs, to impact on another, oxytocin, and thereby close the loop back to changes in behavior. A germline-dependent epigenetic effect is illustrated by maternal or paternal imprinting. Wilkinson and colleagues (Davies et al., 2008) identify imprinted genes as being monoallelically expressed in a parent of origin context. Put more simply, there are some genes in which only one copy is functional, and whether the functional copy is derived from the father or the mother has important consequences for its actions. The effect is achieved by silencing the gene via methylation or histone modification of the gene in the gametes of one parent or the other. There is a preponderance of these genes expressed in the brain (which is among the highest gene-expressing organs in the body) and of the 82 identified to-date, many are critically involved in fundamental processes related to growth and development. The ultimate function of imprinted genes remains a matter of debate, but as reviewed by Wilkinson et al. (Davies et al., 2008), one likely cause is rooted in the battle of the sexes, i.e. the inherent differential investment in future fitness made by profligate males versus resource-defensive females. In humans, Prader–Willi syndrome is a well-characterized example of the potential cost of imprinted genes, and the authors use the phenotype as a paradigm for how epigenetics can have an impact on neuroendocrine functions.
342
Editorial / Frontiers in Neuroendocrinology 29 (2008) 341–343
Table 1 Terminology used in epigenetics Name
Acronym(s)
Description
Acetyl-H3K9 Bisulfite conversion
Ach3K9
Histone-specific antibody A method for detecting sites of methylation of the DNA The combination of nucleotides, histones and associated enzymes Active chromatin Inactive chromatin Site of methylation Require tandem CpG repeats Transfer methyl groups to 50 position of cytosine residues Catalog of epigenetic modifications in the genome Removes acetyl groups from histones Adds acetyl groups
Chromatin Euchromatin Heterochromatin CpGs Differentially methylated regions DNA methyl transferases
CpGs DMRs DNMTs
Epigenome Histone deacetylases Histone acetyl transferases
HDACs HATs
Histone methyl transferases
HMTs
Histones
H2A, H2B, H3 and H4 H1
Imprinted genes MeCP-1 and MeCP-2 Nucleosome
CpG-binding domain proteins
Comments
Places a methyl group on arginine and lysine residues of predominantly H3 and H4 Two of each make an octomer to form the core of the nucleosome Links the intervening sequences between nucleosomes Genes that are monoallelically expressed as a function of parent of origin Specific methylation repressor can recruit HDACs
Critical for imprinting Long-term stable gene silencing
Suppress transcription Enhance transcription, CBP is a transcriptional co-activator and a HAT Generally associated with gene silencing
Further enhance gene silencing
One hundred and forty-seven nucleotide pairs wrapped around an octomer of histones
Keverne and Curley (2008) offer us a view of how both heritable and non-heritable epigenetic effects have played a role in the evolution of the mammalian brain, noting that human identical twins start with similar epigenetic modifications and then diverge with aging. Keverne also offers an alternative explanation for the evolution of imprinting, arguing there is a logical inconsistency in the so-called ‘‘genetic conflict” theory. Emerging evidence suggests the control of imprinting is predominantly matrilineal and many paternally imprinted genes actually become so by the active silencing of the maternal allele in the female. If the advantage of paternal expression is increased growth of the fetus at the cost of the mother, this would suggest the female is actively undermining her own fitness, something evolution tends not to support. A maternal/paternal coadaptive process is proposed and explored as a possible alternative to the genetic conflict theory. Keverne proposes coadaptation occurs between the mother and her offspring and involves a complex interplay of imprinted gene expression in the placenta, maternal hypothalamus and fetal brain to regulate nutrient distribution, maternal care and feeding and the sexual behavior of adult male progeny. A cornerstone of neuroendocrinology is the organizational effect of early steroid exposure to determine sex-specific steroid-mediated adult responses. We have known for close to 50 years that the gonadal steroids, estrogens and androgens, profoundly alter brain development to generate distinct male and female phenotypes. Given that the genotype of every male neuron is different from that of every female neuron, hormones are not an immediately obvious
way to direct sexual differentiation of the brain. Nonetheless, the role of genetics in sex differentiation is largely limited to the gonads, with all subsequent events being above the genome, albeit with emerging exceptions. Because adult gene expression can be impacted by early hormonal events, the process of steroid-mediated sexual differentiation of the brain can be considered epigenetic under the loosest definitions. This concept is further expanded in the review by Gore (Gore, 2008). Citing an additional descriptor of epigenetics—‘‘the study of the mechanisms of temporal and spatial control of gene activity during the development of complex organisms”, Gore artfully argues this concept applies to the field of developmental reproductive neuroendocrinology in that it perfectly encapsulates the concept of coordinated development of the hypothalamic-pituitarygonadal axis and the neural circuits controlling sex-specific reproductive behavior. The review by Wilson (Wilson, 2008) focuses on the endogenous regulation of the ER and highlights the importance of splice variants to produce differences in the promoter region that then direct tissue specific patterns of expression. The mouse ERa promoter has up to six different forms, resulting in at least five mRNA splice variants. Noting that ERa expression in the brain varies both by region and age, Wilson highlights the observation that high levels of ERa in the neonatal mouse (and rat) cortex will decline with advancing age and this decline appears to be intrinsic to the cell, not the result of changing external or afferent influences. She also notes the lack of evidence for factors that increase expression of ERa in the brain, other
Editorial / Frontiers in Neuroendocrinology 29 (2008) 341–343
than pathological manipulations such as ovariectomy, leading her to speculate we must search for something other than the usual suspects when it comes to regulation of ERa levels. Methylation of CpG islands in the promoter region of ERa has been associated with breast cancer and cardiovascular disease and Wilson offers evidence that a similar phenomenon is occurring in the brain. She is now exploring how epigenetic modification of ERa might contribute to normal brain development as well as responses to neuronal injury. The parallels to the work of Champagne are obvious and she appropriately draws them as well as reviewing the potential role of epigenetics in human neurological disorders and diseases. Ruden carries the point of steroid-mediated sexual differentiation as a model of epigenetic effects even further, arguing the increase of endocrine disrupting compounds in the environment could be permanently altering the health of future generations by increasing the risks of cancer (Ruden et al., 2008). He proposes a novel ‘‘neoLamarckian” mechanism for morphological evolution that involves rapid epigenetic assimilation that then sets the stage for future genetic assimilation of morphological changes via directed DNA mutations. He calls the model EDGE for Epigenetically Directed Genetic Error, and proposes this as a mechanism for stabilization of environmentally-induced phenotypes across generations. Ruden has demonstrated the EDGE effect in Drosophila, his organism of study, and uses molecular information available on domestic dogs as a possible case for mammals. Of even
343
greater interest to the readers of Frontiers in Neuroendocrinology is the discussion of possible EDGE effects in a remarkable 50-year project in Russia taming foxes that resulted in profound coordinated behavioral and morphological changes. As a group, these reviews offer a focused yet broad view of epigenetics. Each author has sought to emphasize how epigenetic, endocrine and neural variables intersect and modulate each other. In some cases the endocrine environment is influencing the brain, in others the brain is influencing the endocrine system. The ability of behavior to change the brain to regulate behavior is a principle largely unique to neuroendocrinology and the integration of epigenetic factors into that principle will further illuminate this complex, intriguing and highly relevant research field. Margaret M. McCarthy * Department of Physiology and Psychiatry, University of Maryland School of Medicine, 655 W Baltimore Street, Baltimore, MD 21201-1559, USA E-mail address: [email protected] David Crews Section of Integrative Biology, University of Texas at Austin, USA Available online 1 February 2008
*
Corresponding author. Fax: +1 410 706 8341.
Frontiers in Neuroendocrinology Frontiers in Neuroendocrinology 29 (2008) 341–343 www.elsevier.com/locate/yfrne
Editorial
Epigenetics—New frontiers in neuroendocrinology The NIH (National Institutes of Health, US) Roadmap for biomedical research priorities was implemented in 2002, signaling a sea change in one of the largest sponsors of scientific research in the world. The goal was to identify major opportunities and gaps in research that no one group or institute could tackle alone. Five years later, in early 2007, an update to the roadmap identified Epigenetics as one of two subject areas approved for immediate implementation (http://nihroadmap.nih.gov/roadmap15update. asp). The question is, who will do the implementing? Neuroendocrinology is a cross-cutting discipline by definition and therefore uniquely situated to make major advances in our understanding of the complex interplay between genes, the environment, the brain and behavior. The intent of this special issue of Frontiers in Neuroendocrinology is to acquaint the novice with the topic of epigenetics and its terminology (Table 1), highlight the work that is currently being conducted in the field, and prompt more interest and ultimately research on the role of epigenetic variables in neuroendocrine systems. One of the challenges in epigenetics is how to define it beyond its obvious meaning of ‘‘above genetics”. The NIH defines epigenetics as the study of stable genetic modifications that result in changes in gene expression and function without a corresponding alteration in DNA sequence. The epigenome is a catalog of the epigenetic modifications that occur in the genome. David Crews points out in this issue (Crews, 2008), that definitions such as this do not distinguish between epigenetic changes that are independent of the germline, what he terms ContextDependent epigenetic changes, and Germline-Dependent modification or transmission through a single cell bottleneck, the gametes. Examples of both are included in this issue. Crews further distinguishes epigenetics as being Molecular versus Molar as a way of codifying the level of analysis. The meaning of the former is fairly self-evident, referring to the nuts and bolts, or molecular modifications of the genome (but not the DNA sequence). The latter is a term rooted in functional psychology that encompasses the interactions between cells, physiological and neuroendocrine systems, or individuals and how they are adapted to the social and biotic environments. Both concepts are elaborated on in detail in this issue (Crews, 2008).
0091-3022/$ - see front matter Ó 2008 Elsevier Inc. All rights reserved. doi:10.1016/j.yfrne.2008.01.002
An excellent example of Context-Dependent epigenetic changes is presented in the review by Frances Champagne (Champagne, 2008) of her own and others’ seminal work on the impact of maternal behavior on various aspects of neuronal functioning in the offspring. Mothers who groom their offspring with a low frequency produce changes in the methylation of GC residues in the promoter region of the gene coding for the estrogen receptor (ER) for the lifetime of the young. The consequence of the methylation is to block the transcription of the gene, thereby reducing the amount of estrogen receptor in the preoptic area. This in turn has important consequences for oxytocin receptor expression. Oxytocin is a critical affiliative hormone capable of modulating a wide range of behaviors considered central to mental health and well-being. Thus she provides an elegant example of how behavioral experience can alter gene expression in one system, ERs, to impact on another, oxytocin, and thereby close the loop back to changes in behavior. A germline-dependent epigenetic effect is illustrated by maternal or paternal imprinting. Wilkinson and colleagues (Davies et al., 2008) identify imprinted genes as being monoallelically expressed in a parent of origin context. Put more simply, there are some genes in which only one copy is functional, and whether the functional copy is derived from the father or the mother has important consequences for its actions. The effect is achieved by silencing the gene via methylation or histone modification of the gene in the gametes of one parent or the other. There is a preponderance of these genes expressed in the brain (which is among the highest gene-expressing organs in the body) and of the 82 identified to-date, many are critically involved in fundamental processes related to growth and development. The ultimate function of imprinted genes remains a matter of debate, but as reviewed by Wilkinson et al. (Davies et al., 2008), one likely cause is rooted in the battle of the sexes, i.e. the inherent differential investment in future fitness made by profligate males versus resource-defensive females. In humans, Prader–Willi syndrome is a well-characterized example of the potential cost of imprinted genes, and the authors use the phenotype as a paradigm for how epigenetics can have an impact on neuroendocrine functions.
342
Editorial / Frontiers in Neuroendocrinology 29 (2008) 341–343
Table 1 Terminology used in epigenetics Name
Acronym(s)
Description
Acetyl-H3K9 Bisulfite conversion
Ach3K9
Histone-specific antibody A method for detecting sites of methylation of the DNA The combination of nucleotides, histones and associated enzymes Active chromatin Inactive chromatin Site of methylation Require tandem CpG repeats Transfer methyl groups to 50 position of cytosine residues Catalog of epigenetic modifications in the genome Removes acetyl groups from histones Adds acetyl groups
Chromatin Euchromatin Heterochromatin CpGs Differentially methylated regions DNA methyl transferases
CpGs DMRs DNMTs
Epigenome Histone deacetylases Histone acetyl transferases
HDACs HATs
Histone methyl transferases
HMTs
Histones
H2A, H2B, H3 and H4 H1
Imprinted genes MeCP-1 and MeCP-2 Nucleosome
CpG-binding domain proteins
Comments
Places a methyl group on arginine and lysine residues of predominantly H3 and H4 Two of each make an octomer to form the core of the nucleosome Links the intervening sequences between nucleosomes Genes that are monoallelically expressed as a function of parent of origin Specific methylation repressor can recruit HDACs
Critical for imprinting Long-term stable gene silencing
Suppress transcription Enhance transcription, CBP is a transcriptional co-activator and a HAT Generally associated with gene silencing
Further enhance gene silencing
One hundred and forty-seven nucleotide pairs wrapped around an octomer of histones
Keverne and Curley (2008) offer us a view of how both heritable and non-heritable epigenetic effects have played a role in the evolution of the mammalian brain, noting that human identical twins start with similar epigenetic modifications and then diverge with aging. Keverne also offers an alternative explanation for the evolution of imprinting, arguing there is a logical inconsistency in the so-called ‘‘genetic conflict” theory. Emerging evidence suggests the control of imprinting is predominantly matrilineal and many paternally imprinted genes actually become so by the active silencing of the maternal allele in the female. If the advantage of paternal expression is increased growth of the fetus at the cost of the mother, this would suggest the female is actively undermining her own fitness, something evolution tends not to support. A maternal/paternal coadaptive process is proposed and explored as a possible alternative to the genetic conflict theory. Keverne proposes coadaptation occurs between the mother and her offspring and involves a complex interplay of imprinted gene expression in the placenta, maternal hypothalamus and fetal brain to regulate nutrient distribution, maternal care and feeding and the sexual behavior of adult male progeny. A cornerstone of neuroendocrinology is the organizational effect of early steroid exposure to determine sex-specific steroid-mediated adult responses. We have known for close to 50 years that the gonadal steroids, estrogens and androgens, profoundly alter brain development to generate distinct male and female phenotypes. Given that the genotype of every male neuron is different from that of every female neuron, hormones are not an immediately obvious
way to direct sexual differentiation of the brain. Nonetheless, the role of genetics in sex differentiation is largely limited to the gonads, with all subsequent events being above the genome, albeit with emerging exceptions. Because adult gene expression can be impacted by early hormonal events, the process of steroid-mediated sexual differentiation of the brain can be considered epigenetic under the loosest definitions. This concept is further expanded in the review by Gore (Gore, 2008). Citing an additional descriptor of epigenetics—‘‘the study of the mechanisms of temporal and spatial control of gene activity during the development of complex organisms”, Gore artfully argues this concept applies to the field of developmental reproductive neuroendocrinology in that it perfectly encapsulates the concept of coordinated development of the hypothalamic-pituitarygonadal axis and the neural circuits controlling sex-specific reproductive behavior. The review by Wilson (Wilson, 2008) focuses on the endogenous regulation of the ER and highlights the importance of splice variants to produce differences in the promoter region that then direct tissue specific patterns of expression. The mouse ERa promoter has up to six different forms, resulting in at least five mRNA splice variants. Noting that ERa expression in the brain varies both by region and age, Wilson highlights the observation that high levels of ERa in the neonatal mouse (and rat) cortex will decline with advancing age and this decline appears to be intrinsic to the cell, not the result of changing external or afferent influences. She also notes the lack of evidence for factors that increase expression of ERa in the brain, other
Editorial / Frontiers in Neuroendocrinology 29 (2008) 341–343
than pathological manipulations such as ovariectomy, leading her to speculate we must search for something other than the usual suspects when it comes to regulation of ERa levels. Methylation of CpG islands in the promoter region of ERa has been associated with breast cancer and cardiovascular disease and Wilson offers evidence that a similar phenomenon is occurring in the brain. She is now exploring how epigenetic modification of ERa might contribute to normal brain development as well as responses to neuronal injury. The parallels to the work of Champagne are obvious and she appropriately draws them as well as reviewing the potential role of epigenetics in human neurological disorders and diseases. Ruden carries the point of steroid-mediated sexual differentiation as a model of epigenetic effects even further, arguing the increase of endocrine disrupting compounds in the environment could be permanently altering the health of future generations by increasing the risks of cancer (Ruden et al., 2008). He proposes a novel ‘‘neoLamarckian” mechanism for morphological evolution that involves rapid epigenetic assimilation that then sets the stage for future genetic assimilation of morphological changes via directed DNA mutations. He calls the model EDGE for Epigenetically Directed Genetic Error, and proposes this as a mechanism for stabilization of environmentally-induced phenotypes across generations. Ruden has demonstrated the EDGE effect in Drosophila, his organism of study, and uses molecular information available on domestic dogs as a possible case for mammals. Of even
343
greater interest to the readers of Frontiers in Neuroendocrinology is the discussion of possible EDGE effects in a remarkable 50-year project in Russia taming foxes that resulted in profound coordinated behavioral and morphological changes. As a group, these reviews offer a focused yet broad view of epigenetics. Each author has sought to emphasize how epigenetic, endocrine and neural variables intersect and modulate each other. In some cases the endocrine environment is influencing the brain, in others the brain is influencing the endocrine system. The ability of behavior to change the brain to regulate behavior is a principle largely unique to neuroendocrinology and the integration of epigenetic factors into that principle will further illuminate this complex, intriguing and highly relevant research field. Margaret M. McCarthy * Department of Physiology and Psychiatry, University of Maryland School of Medicine, 655 W Baltimore Street, Baltimore, MD 21201-1559, USA E-mail address: [email protected] David Crews Section of Integrative Biology, University of Texas at Austin, USA Available online 1 February 2008
*
Corresponding author. Fax: +1 410 706 8341.