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The Epigenetic Switches for Neural Development and Psychiatric Disorders
Available online at www.sciencedirect.com
Journal of Genetics and Genomics 40 (2013) 339e346
JGG REVIEW
The Epigenetic Switches for Neural Development and Psychiatric Disorders Jingwen Lv b, Yongjuan Xin a, Wenhao Zhou b,*, Zilong Qiu a,* a
Institute of Neuroscience, Shanghai Institute of Biological Sciences, Chinese Academy of Sciences, Shanghai 200031, China b Department of Neonatology, Children’s Hospital of Fudan University, Shanghai 201102, China Received 26 January 2013; revised 19 April 2013; accepted 30 April 2013 Available online 9 May 2013
ABSTRACT The most remarkable feature of the nervous system is that the development and functions of the brain are largely reshaped by postnatal experiences, in joint with genetic landscapes. The nature vs. nurture argument reminds us that both genetic and epigenetic information is indispensable for the normal function of the brain. The epigenetic regulatory mechanisms in the central nervous system have been revealed over last a decade. Moreover, the mutations of epigenetic modulator genes have been shown to be implicated in neuropsychiatric disorders, such as autism spectrum disorders. The epigenetic study has initiated in the neuroscience field for a relative short period of time. In this review, we will summarize recent discoveries about epigenetic regulation on neural development, synaptic plasticity, learning and memory, as well as neuropsychiatric disorders. Although the comprehensive view of how epigenetic regulation contributes to the function of the brain is still not completed, the notion that brain, the most complicated organ of organisms, is profoundly shaped by epigenetic switches is widely accepted. KEYWORDS: DNA methylation; Adult neurogenesis; Neural plasticity; Learning and memory; Autism; Depression
INTRODUCTION
Abbreviations: AML, acute myeloid leukemia; Avp, arginine vasopressin; BDNF, brain-derived neurotrophic factor; CBP, CREB-binding protein; CNS, central nervous system; CREB, cAMP response element-binding protein; CREST, calcium-responsive transactivator; DG, dentate gyrus; Dnmt1, DNA methyltransferase 1; Dnmt3a, DNA methyltransferase 3a; GADD45b, growth arrest and DNA-damage-inducible, beta; GluR2, glutamate receptor 2; HDAC, histone deacetylase; HDAC2, histone deacetylase 2; JAK, Janus kinase; MeCP2, methyl CpG binding protein 2; mEPSC, miniature excitatory postsynaptic current; miR-132, mircroRNA-132; MND, motor neuron diseases; PP1, protein phosphatase 1; REST, RE1-silencing transcription factor; SMA, spinal muscular atrophy; STAT, signal transducer and activator of transcription; TET1, ten-eleven translocation 1. * Corresponding authors. Tel: þ86 21 5492 1806, fax: þ86 21 5492 1735 (Z. Qiu); Tel/fax: þ86 21 6493 1003 (W. Zhou). E-mail addresses: [email protected] (W. Zhou); [email protected]. cn (Z. Qiu).
The unique feature of the central nervous system (CNS) is that the developmental process of the brain is largely regulated by experience inputs. In 1960s, Hubel and Wiesel found that deprivation of visual inputs on neonatal cats for a certain period of time would lead to the loss of vision in adulthood (Hubel and Wiesel, 1998). The following gene expression profiling studies indeed identified dramatic changes in gene expression patterns, which immediately raise the possibility that epigenetic regulatory mechanisms may play constructive roles in controlling neural development by means of regulating gene expression (Majdan and Shatz, 2006; Tropea et al., 2006). Experience-dependent gene expression events happened in the neuron are essential processes during which the neuron modifies its properties to adapt outside environments. Molecular biology studies since 1980s have identified numerous
1673-8527/$ - see front matter Copyright Ó 2013, Institute of Genetics and Developmental Biology, Chinese Academy of Sciences, and Genetics Society of China. Published by Elsevier Limited and Science Press. All rights reserved. http://dx.doi.org/10.1016/j.jgg.2013.04.007
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critical neural activity-dependent transcriptional regulators, such as cAMP responsive element-binding protein (CREB), CREB-binding protein (CBP) and calcium-responsive transactivator (CREST) (Qiu and Ghosh, 2008a, 2008b). Interestingly, CBP, one of the most critical transcriptional activators in the neuron, contains histone acetylation activity itself. Thus epigenetic studies including histone acetylation became to be one of themes in neuroscience field. Epigenetic regulatory mechanisms are involved in many aspects of formation and function of the nervous system. One of the first important steps of neural development is the generation of a variety of cell types in the brain. We will focus on discussing the epigenetic regulation during neurogenesis and gliogenesis. Next, we will discuss the epigenetic regulation of hippocampal neurogenesis in the adult animal, which plays a critical role in regulating cognitive functions. Epigenetic regulation plays a decisive role not only in neuronal fate determination, but also in neural plasticity process. The acquirement and retrieval of memory are believed to rely on epigenetic regulation of genetic switches on the genome to a large extent. Finally, in this review, we will discuss an important issue that mutations of epigenetic regulator genes are found to associate with neuropsychiatric disorders, such as autism spectrum disorders. The connection between epigenetic regulation and psychiatric disorders has attracted attentions of experts across epigenetics, neuroscience and neurology fields over the last few years. In the end, we will raise the unanswered questions and provide perspectives for the future epigenetic study in neuroscience field. EPIGENETIC CONTROL OF NEURAL DEVELOPMENT The formation of the CNS primarily depends on the genetic information stored in the genome. Nevertheless, epigenetic mechanisms via DNA methylation and histone modification are found to be essential for the expression of genes required for various steps during neural development, including neurogenesis and gliogenesis. Here, we will discuss three main events in which epigenetic regulation plays important roles discovered recently. Neurogenesis and fate determination DNA methylation and demethylation are critical switches for gene expression. The discovery that neuronal genes are repressed in non-neuronal cell by repressor element 1 silencing transcription factor (REST)-dependent DNA methylation events showed an important mechanism which neurogenesis may require (Chong et al., 1995; Lunyak et al., 2002; Ballas et al., 2005). Although the REST-dependent epigenetic switch is known to be responsible for repressing neuronal genes in non-neuronal cells, interestingly, RodenasRuano and colleagues found that the developmental expression of glutamatergic receptor subunits in the post-mitotic neurons is also regulated by REST-dependent DNA methylation (Rodenas-Ruano et al., 2012). This report provides
important insights that DNA methylation related epigenetic regulation may play a critical role in neurons during neural development as well. There are several critical steps after neurogenesis, including migration of post-mitotic neurons, dendritic and axonal morphogenesis, and initial formation of synapses. It is critical to address whether DNA methylation may be involved in these physiological processes. It is critical to address whether and how DNA methylation switches are modulated during neurogenesis. However, DNA methyltransferase 3a (Dnmt3a) is found to be required for neurogenesis in the following studies. Wu and colleagues identified an un-expected mechanism for the role of Dnmt3a in neurogenesis (Wu et al., 2010). Using genome-wide chromatin immunoprecipitation, they found that Dnmt3a mainly occupies intergenic and non-proximal promoter regions of active transcribed genes. They showed that the presence of Dnmt3a in non-proximal regions of neurogenic genes is required for their normal expression. Interestingly, the Dnmt3a-dependent methylation of non-proximal regions of neurogenic genes seems to antagonize the repression activity of a critical transcriptional repressor Polycomb, thus maintaining the active transcription of neurogenic genes (Wu et al., 2010). This novel mechanism provides important insights of epigenetic regulation of neurogenesis. The generation of glia, another critical component of the nervous system, is also regulated by DNA methylation mechanisms. The Janus kinase (JAK)-signal transducer and activator of transcription (STAT) signaling pathway have been shown to be implicated in gliogenesis. Fan and colleagues found that the genetic deletion of DNA methyltransferase 1 (Dnmt1), a critical DNA methyltransferase in the nervous system, leads to premature glia differentiation. They found that methylation of certain JAK-STAT pathway genes is required for controlling gliogenesis in the correct timing. Loss of Dnmt1 and DNA methylation control therefore leads to abnormal expression of gliogenic genes (Fan et al., 2005). Thus, epigenetic regulations involving DNA methylation are found to be crucial for the fate determination of neuron and glia in the nervous system (Hamby et al., 2008; Coskun et al., 2012). An important question that needs to be answered next is whether and how epigenetic switches during neurogenesis and gliogenesis could be regulated by experience-dependent outside inputs. Would experience input received by organisms be able to influence the building landscape of the nervous system? Given the current discoveries that epigenetic switches are deeply controlled by environmental stimulus, we would like to propose the hypothesis that the generation of neuron and glia in the nervous system may also be regulated by the environment inputs via epigenetic regulatory mechanisms. Adult hippocampal neurogenesis One of the interesting properties of the CNS is that new neurons could be continuously generated throughout the adulthood, which is called adult neurogenesis. There are two regions in the brain where adult neurogenesis occurs,
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i.e., dentate gyrus (DG) of the hippocampus and olfactory bulb (Zhao et al., 2008; Suh et al., 2009; Aimone et al., 2011). Neuronal activity has been found to be associated with neurogenesis in the DG previously. Ma and colleagues found that the neural activity would lead to rapid expression of a gene called growth arrest and DNA-damage-inducible 45b (Gadd45b) (Ma et al., 2009). Importantly, they found that Gadd45b is required for the activity-induced proliferation of neural progenitor cells and activity-induced gene expression in the DG. It turns out that Gadd45b is required for the demethylation of promoters of critical genes responsible for new-born neuron development, such as brain-derived neurotrophic factor (BDNF). The electric stimulus that would enhance neurogenesis in DG has less effects on Gadd45b knockout mice. This critical study identified an important epigenetic regulator that plays a critical role in regulating adult neurogenesis in response to environment stimulus (Faigle and Song, 2012). In another report, the same research group used chromatin immunoprecipitation combined with microarray methods to measure the global change of DNA methylation in DG upon neural activity. Surprisingly, they found around 1.4% CpG islands in DG neurons are actively methylated and demethylated upon electric shock, which is higher than previous thought (Guo et al., 2011). This study provides a more comprehensive view about DNA methylation profiling happened in genomes of post-mitotic neurons and further suggests that the methylation status of post-mitotic neurons is not as static as previously hypothesized. More interestingly, electric shock equipment used in these studies has therapeutic effects to human patients with depression and other psychiatric disorders, which raises the possibility that epigenetic regulatory mechanisms may play important role in pathophysiology of neuropsychiatric disorders. Guo and coworkers showed that the expression of Dnmt3a is up-regulated by neural activity caused by electric shock equipment (Guo et al., 2011). However, in another study, Miller and colleagues found that Dnmt3a is regulated by a neuronal-specific microRNAemiR-132, which is up-regulated by neural activity (Klein et al., 2007; Magill et al., 2010; Miller et al., 2012). These controversial findings suggest that the regulatory mechanisms for the expression of Dnmt3a in neuron may include multiple mechanisms. Thus, it will be of great interest to elucidate the molecular mechanisms of controlling Dnmt3a expression in post-mitotic neurons (Fig. 1). The DNA active demethylation mechanisms including teneleven translocation (Tet)-dependent 5 mC hydroxylation have been revealed recently (He et al., 2011; Ito et al., 2011). Indeed, Guo and colleagues also found that ten-eleven translocation 1 (Tet1) plays a critical role in mediating DNA demethylation process in post-mitotic neurons in hippocampal DG region upon neural activity caused by electric shock (Guo et al., 2011a, 2011b). They showed that Tet1 is required for neural activity-induced DNA demethylation and therefore activity-dependent gene expression. But that leaves us some interesting questions: What is the switch to turn on the Tet1 activity upon neural activity? Whether Tet1 expression level is up-regulated by neural activity? Or is Tet1 modified by
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post-translational modifications such as phosphorylation? These questions are critical for us to further understand how environment stimuli trigger DNA active demethylation process in the nervous system. Neuronal apoptosis and neurodegenerative disorders The massive neuronal apoptosis takes place during neural development (Nijhawan et al., 2000). Moreover, abnormal neuronal death is closely associated with neurodegenerative disorders, such as Alzheimer’s and Parkinson’s disease (Kwok, 2010; Hwang et al., 2013). Thus, the common epigenetic regulatory mechanisms identified in other systems are most likely shared in the nervous system. Recently, the studies of motor neuron diseases (MND) and spinal muscular atrophy (SMA) strongly suggest that the abnormal death of motor neurons may lead to severe disorders (Lunke and El-Osta, 2009). An interesting study by Chestnut and colleagues identified a role for DNA methylation in motor neuron death (Chestnut et al., 2011). They found that introduction of Dnmt3a could induce neuronal cell death using cultured motor neuron in vitro. Therefore, inhibition of DNA methylation pharmacologically could promote motor neuron survival under apoptotic stimulus. This report is of special benefits to current mechanisms and potential therapeutic studies about MND. Whether manipulations of DNA methylation would have effects on treatment of MND? DNA methylation blockers have been used for certain cancer like acute myeloid leukemia (AML). Whether or not the similar therapy may have effects on MND would have immediate clinical significance. EPIGENETIC CONTROL OF SYNAPTIC PLASTICITY The molecular mechanisms for learning and memory include proper gene expression induced by environmental stimuli. The learning induced gene expression and protein synthesis are required for memory achievement and retrieval (Squire and Barondes, 1970; Segal et al., 1971). Therefore, learning-induced epigenetic regulatory mechanisms are inevitably involved in the formation, store and retrieval of memory. Indeed, studies from last few years have accumulated compelling evidences that both DNA methylation and histone acetylation play pivotal roles in controlling learning and memory. DNA methylation in learning and memory Genetic studies by Feng and colleagues showed that both Dnmt1 and Dnmt3a are required for learning and memory, as well as hippocampal synaptic plasticity (Feng et al., 2010). This is a critical study showing that DNA methylation events in the mature nervous system are critical for the normal function. They used genetics methods to knockout Dnmt1 and Dnmt3a in the post-mitotic forebrain neurons of mouse. They found that only deletion of both Dnmt1 and Dnmt3a could lead
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Fig. 1. Signaling pathway for regulating Dnmt3a expression in post-mitotic neurons. Calcium influx in neurons activates CaMKIV, which actives CREB and then stimulates the expression of miR-132. The up-regulation of miR-132 will target Dnmt3a mRNA and result in down-regulation of Dnmt3a protein. CaMKIV, calmodulin-dependent kinase IV; CREB, cAMP responsive element-binding protein.
to deficiency in learning and memory, suggesting that the DNA methylation mechanisms in mature neurons required both Dnmt1 and Dnmt3. This finding is of particular interest since Dnmt1 was found to be critical for maintenance of DNA methylation and might not be required for active DNA methylation. Thus, there are unknown mechanisms in the nervous system that are responsible for DNA methylation in response to learning-induced activity. Interestingly, the DNMT protein level was found to be upregulated during the fear conditioning (Miller and Sweatt, 2007). A memory suppressor gene protein phosphatase 1 (PP1) was repressed by rapid DNA methylation mechanisms. It is important to address whether the enhanced DNA methylation associated with fear conditioning is global across the genome or only happens in certain regions. Miller and colleagues reported that calcineurin, another critical gene involved in learning and memory, is also regulated by hippocampus-dependent associative learning stimulus (Miller et al., 2010). Strikingly, they showed that pharmacological blockade of DNA methylation one month after memory acquirement is still able to disrupt the retrieval of remote memory. These results strongly suggest that DNA methylation event indeed plays a critical role in regulating memory formation and retrieval (Day and Sweatt, 2010, 2011). However, considering the complexity of neural circuitry involved in learning and memory, it is important to address the molecular mechanisms underlying DNA methylation regulated memory formation and retrieval. Several critical questions remain to be answered, such as whether learning-induced DNA methylation is a global effect, in which neuronal populations learninginduced DNA methylation happens, and how neural activity turned on DNA methylation machinery specifically.
Histone modification in learning and memory Another critical epigenetic regulation is modification of histone proteins. There are several important publications over the last few years about the role of histone modification in learning and memory. Initially, Fischer and colleagues used histone deacetylase (HDAC) inhibitors to study whether blocking HDAC may alleviate the cognitive defects in a mouse model of Alzheimer’s diseases (Fischer et al., 2007). They found that HDAC inhibitors exhibited positive effects on mice with cognitive deficit. Moreover, they found that HDAC inhibitors also have effects on wild type animals and showed cognitive enhancement of wild type mice being given HDAC inhibitors. In the following studies, Guan and colleagues found that histone deacetylase 2 (HDAC2), one of the major histone deacetylase, plays a negative role in regulating learning and memory. The gain- and loss-of-function experiments showed that HDAC2 is a critical modulator for memory formation and synaptic plasticity (Guan et al., 2009). Still, the unanswered questions that need to be addressed in the further studies include, but not limited to, the mechanism of HDAC2regulating synaptic plasticity, whether HDAC2 contributes to particular neural circuitry and how histone acetylation interplays with DNA methylation in the memory formation and synaptic plasticity. The same research group went on to show that Sirt1, a histone acetylase, plays a negative role in memory formation (Gao et al., 2010). Interestingly, they found that Sirt1 promotes the expression of a critical micoRNAemiR-134, which targets the critical activity-dependent transcriptional factoreCREB essential for learning and memory (Silva et al., 1998). Thus, Sirt1 plays a negative role in memory formation by a Sirt1-
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miR-134-CREB signaling pathway. These results deliver important message that histone acetylation plays a dynamic role in controlling memory formation and synaptic plasticity. However, it is still too early to draw the conclusion about how histone acetylation or deacetylation plays certain roles on learning and memory without knowing whether the effects of HDAC2 and Sirt1 are general or specific to particular genes (Graff and Tsai, 2013). NEUROPSYCHIATRIC DISORDERS Since the wide involvement of epigenetic regulation in many aspects of neural development and plasticity, it is important to ask whether genetic mutations associated with epigenetic regulators may be linked to disorders of the nervous system. Recently, accumulated evidences have implicated the roles of the epigenetic factors in neuropsychiatric disorders. Here, we will particularly focus on two critical neuropsychiatric disorders, autism spectrum disorders and major depression disorders. MeCP2 and autism spectrum disorders Autism spectrum disorders are a group of neurodevelopmental disorders, characterized by deficiency in social communication and language development. The studies of Rett syndrome, one of severe forms of autism spectrum disorders, provide important insights about epigenetic regulation of autism spectrum disorders. The Rett syndrome was characterized in 1960s by Dr. Rett (1966). This developmental delay disorder is usually associated with girls and the main genetic cause of Rett syndrome was found to be the dysfunction of a single gene methyl CpG binding protein 2 (MeCP2) identified in 1999 (Amir et al., 1999). MeCP2 gene was initially cloned to encode a methyl CpG binding protein, which plays a critical role in repressing gene expression by recruiting HDAC complex (Lewis et al., 1992; Nan et al., 1998). More interestingly, the duplications of genomic locus including mecp2 have been found in autism patients (Ramocki et al., 2009). Thus both loss- and gain-of-function of MeCP2 could lead to defects in neural development and yield psychiatric symptoms (Chahrour and Zoghbi, 2007; Guy et al., 2011). The identification of MeCP2 as the genetic cause for Rett syndrome immediately attracted wide interests across many fields including epigenetics, neuroscience and psychiatrics. What role may MeCP2 play as an epigenetic regulator in the pathology of autism spectrum disorders? Two studies in 2003 provide important insights of the role of MeCP2 in regulating gene expression in the nervous system (Chen et al., 2003; Martinowich et al., 2003). Both groups found that MeCP2 binds to the CpG islands on the promoter of BDNF gene, an important neurotrophic factor, and the activity of neuron rapidly induces the dissociation between MeCP2 and BDNF promoter, which allows the expression of BDNF in response to neural activity. Calcium influx induced by neural activity lead to the phosphorylation of MeCP2 on Serine 421 site, which is
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required for the release of MeCP2 from BDNF promoter. Zhou and coworkers found that the phosphorylation of Serine 421 site of MeCP2 plays a critical role in regulating the development of hippocampal dendritic spines, the mature form of excitatory synapses (Zhou et al., 2006). More functional studies showed that MeCP2 in the neuron is responsible for modulating global state of the chromatin (Skene et al., 2010). Qiu and colleagues found that MeCP2 represses the expression of glutamate receptor 2 (GluR2), a critical subunit of glutamatergic receptors in response to neural activity (Qiu et al., 2012). The repression of GluR2 by MeCP2 upon neural activity is a homeostatic response in the neuron. When neurons are activated by neurotransmitters such as glutamate, the fire rate of neuron will increase, which leads to the MeCP2-dependent repression of GluR2. Loss of GluR2 in turn down-regulates the strength of the synapse and activity of the neuron. This negative feedback is essential for maintenance of neural network. Importantly, Qiu and coworkers showed that this homeostatic response is disrupted in mecp2 knockout mouse, which is the mouse model for Rett syndrome (Qiu et al., 2012). Following studies also identified the key role of MeCP2 in other form of synaptic homeostatic plasticity (Zhong et al., 2012; Blackman et al., 2012). These findings provide important insights about the epigenetic regulation mediated by MeCP2, which is critical for the stability control of the neural network and further suggests that the disruption of neural network stability may be the key contribution factor of autism spectrum disorder pathophysiology (Fig. 2). Researchers have made various animal models for studying the role of MeCP2 in neural development and plasticity. Severe cognitive defects are found in mecp2 knockout mice, suggesting that the mecp2 null mouse serves as a valuable model for mimicking Rett syndrome (Moretti et al., 2006). Since the developmental plasticity of the brain is gradually decreasing during adulthood, the critical question from clinical perspectives is whether the nervous system without mecp2 would be still able to recover if MeCP2 is re-introduced after infant stage, when Rett syndrome is usually diagnosed. Guy and colleagues used sophisticated mouse genetics methods to show that reintroduction of MeCP2 into mecp2 null mouse during adulthood lead to full recovery of the mice with severe phenotypes (Guy et al., 2007). This study is particularly important for the therapeutic study of Rett syndrome and also raises interesting questions how the adult brain still fully recovers after passing early developmental stages. Moreover, it is suggested that epigenetic regulation may play an even more important role in therapeutic efforts for psychiatric disorders, given the fact that epigenetic manipulations could work during adulthood. Experience-dependent epigenetic modulation and depression It is worth notice that the depression symptoms are found to associate with family members of autism patients with MeCP2
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Fig. 2. Homeostatic signaling pathway mediated by MeCP2. When neuron receives stimulus, intracellular CaMKIV-mediated signaling pathway is activated, which results in the activation of CREST-containing transcriptional complex and promotes the expression of MeCP2. MeCP2 in turn represses the expression of GluR2 which leads to the inhibition of mEPSC and homeostatic regulation of neuronal excitability. CaMKIV, calmodulin-dependent kinase IV; CREST, calcium-responsive transactivator; MeCP2, methyl CpG binding protein 2; GluR2, glutamate receptor 2; mEPSC, miniature excitatory postsynaptic current.
genomic duplications (Ramocki et al., 2009). Whether MeCP2 is directly involved in depression disorders is an important question needs to be addressed. Hutchinson and colleagues found that antidepressant administration induces rapid phosphorylation of MeCP2 on Serine 421 site in lateral habenula region in the brain and the mice carrying the MeCP2 phosphorylation deficient mutant S421A appear to have more depressive phenotypes in force swimming and tail suspension tests as compared to wild type mice. Thus, this study indicates that phosphorylation of MeCP2 on Serine 421 site plays an endogenous role in the response of depressive stimulus and the physiological responses of antidepressants. Whether epigenetic modulations may play roles in other forms of stress response? Murgatroyd and colleagues found that early-life stress in mice led to abnormal level of corticosterone and behavior alternations associated with depression (Murgatroyd et al., 2009). Interestingly, they found that the activity-dependent expression of arginine vasopressin (Avp), a critical hormone for stress response, was regulated by MeCP2 and therefore early-life stress induced abnormal regulation of Avp expression mediated by MeCP2. This finding showed that epigenetic regulations are critical for prolonged responses of stress stimuli. Whether DNA methylation and histone modifications would be involved in epigenetic modulations for stress response in either acute or prolonged period would be interesting questions to address. Considering the different time scales of DNA methylation and histone modifications, they may play distinct roles in regulating stress responses (Massart et al., 2012; Nishioka et al., 2012).
CONCLUDING REMARKS AND PERSPECTIVES Taken together, it is recognized that epigenetic regulator mechanisms are significant switches for the neural development and plasticity, as well as disorders. Regarding to further studies, it is important that biochemical discovery could be more closely linked to physiological relevance. Moreover, it is essential to realize that the brain is a complicated organ composed by billions of cells and even more neural connections. Therefore, the role a single gene may play must be interpreted under the scape of various cell types and different neural circuitries. However, if animal carrying a single gene mutation, which is involved in epigenetic regulation, appears to have cognitive effects, but without knowing which neural circuitry is actually affected, the knowledge we learn will be very limited. The available mouse genetics methods offer good tools to manipulate specific neural circuitry with precise timing control. Thus the further study must take advantage of the progress in mouse genetics methods to address the role of epigenetic regulators in neural development and plasticity. Moreover, we hope that the specific feature of epigenetic regulation should not be omitted. Epigenetic control may serve as the bridge of connecting environmental inputs with genetic switches and play a central role in mediating the prolonged physiological responses of organisms. Finally, there are two surprising reports published very recently showing that stress from early age could lead to prolonged behavioral consequences by epigenetic control of the gene expression of dopamine synthesis enzyme via glucocorticoid signaling
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pathway (Barik et al., 2013; Niwa et al., 2013). This will shed new lights on the epigenetic research in neuroscience field and provide new routes through which mechanistic studies on complicated physiological responses of organisms by epigenetic regulation could be performed. ACKNOWLEDGEMENTS This work was supported by the grant from the National Natural Science Foundation of China (the Fostering Project of the Major Research) (No. 91232712). REFERENCES Aimone, J.B., Deng, W., Gage, F.H., 2011. Resolving new memories: a critical look at the dentate gyrus, adult neurogenesis, and pattern separation. Neuron 70, 589e596. Amir, R.E., Van den Veyver, I.B., Wan, M., Tran, C.Q., Francke, U., Zoghbi, H.Y., 1999. Rett syndrome is caused by mutations in X-linked MECP2, encoding methyl-CpG-binding protein 2. Nat. Genet. 23, 185e188. Ballas, N., Grunseich, C., Lu, D.D., Speh, J.C., Mandel, G., 2005. REST and its corepressors mediate plasticity of neuronal gene chromatin throughout neurogenesis. Cell 121, 645e657. Barik, J., Marti, F., Morel, C., Fernandez, S.P., Lanteri, C., Godeheu, G., Tassin, J.P., Mombereau, C., Faure, P., Tronche, F., 2013. Chronic stress triggers social aversion via glucocorticoid receptor in dopaminoceptive neurons. Science 339, 332e335. Blackman, M.P., Djukic, B., Nelson, S.B., Turrigiano, G.G., 2012. A critical and cell-autonomous role for MeCP2 in synaptic scaling up. J. Neurosci. 32, 13529e13536. Chahrour, M., Zoghbi, H.Y., 2007. The story of Rett syndrome: from clinic to neurobiology. Neuron 56, 422e437. Chen, W.G., Chang, Q., Lin, Y., Meissner, A., West, A.E., Griffith, E.C., Jaenisch, R., Greenberg, M.E., 2003. Derepression of BDNF transcription involves calcium-dependent phosphorylation of MeCP2. Science 302, 885e889. Chestnut, B.A., Chang, Q., Price, A., Lesuisse, C., Wong, M., Martin, L.J., 2011. Epigenetic regulation of motor neuron cell death through DNA methylation. J. Neurosci. 31, 16619e16636. Chong, J.A., Tapia-Ramirez, J., Kim, S., Toledo-Aral, J.J., Zheng, Y., Boutros, M.C., Altshuller, Y.M., Frohman, M.A., Kraner, S.D., Mandel, G., 1995. REST: a mammalian silencer protein that restricts sodium channel gene expression to neurons. Cell 80, 949e957. Coskun, V., Tsoa, R., Sun, Y.E., 2012. Epigenetic regulation of stem cells differentiating along the neural lineage. Curr. Opin. Neurobiol. 22, 762e767. Day, J.J., Sweatt, J.D., 2010. DNA methylation and memory formation. Nat. Neurosci. 13, 1319e1323. Day, J.J., Sweatt, J.D., 2011. Epigenetic mechanisms in cognition. Neuron 70, 813e829. Faigle, R., Song, H., 2012. Signaling mechanisms regulating adult neural stem cells and neurogenesis. Biochim. Biophys. Acta 1830, 2435e2448. Fan, G., Martinowich, K., Chin, M.H., He, F., Fouse, S.D., Hutnick, L., Hattori, D., Ge, W., Shen, Y., Wu, H., Ten, H.J., Shuai, K., Sun, Y.E., 2005. DNA methylation controls the timing of astrogliogenesis through regulation of JAK-STAT signaling. Development 132, 3345e3356. Feng, J., Zhou, Y., Campbell, S.L., Le, T., Li, E., Sweatt, J.D., Silva, A.J., Fan, G., 2010. Dnmt1 and Dnmt3a maintain DNA methylation and regulate synaptic function in adult forebrain neurons. Nat. Neurosci. 13, 423e430. Fischer, A., Sananbenesi, F., Wang, X., Dobbin, M., Tsai, L.H., 2007. Recovery of learning and memory is associated with chromatin remodelling. Nature 447, 178e182.
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Gao, J., Wang, W.Y., Mao, Y.W., Graff, J., Guan, J.S., Pan, L., Mak, G., Kim, D., Su, S.C., Tsai, L.H., 2010. A novel pathway regulates memory and plasticity via SIRT1 and miR-134. Nature 466, 1105e1109. Graff, J., Tsai, L.H., 2013. The potential of HDAC inhibitors as cognitive enhancers. Annu. Rev. Pharmacol. Toxicol. 53, 311e330. Guan, J.S., Haggarty, S.J., Giacometti, E., Dannenberg, J.H., Joseph, N., Gao, J., Nieland, T.J., Zhou, Y., Wang, X., Mazitschek, R., Bradner, J.E., DePinho, R.A., Jaenisch, R., Tsai, L.H., 2009. HDAC2 negatively regulates memory formation and synaptic plasticity. Nature 459, 55e60. Guo, J.U., Ma, D.K., Mo, H., Ball, M.P., Jang, M.H., Bonaguidi, M.A., Balazer, J.A., Eaves, H.L., Xie, B., Ford, E., Zhang, K., Ming, G.L., Gao, Y., Song, H., 2011. Neuronal activity modifies the DNA methylation landscape in the adult brain. Nat. Neurosci. 14, 1345e1351. Guo, J.U., Su, Y., Zhong, C., Ming, G.L., Song, H., 2011a. Emerging roles of TET proteins and 5-hydroxymethylcytosines in active DNA demethylation and beyond. Cell Cycle 10, 2662e2668. Guo, J.U., Su, Y., Zhong, C., Ming, G.L., Song, H., 2011b. Hydroxylation of 5methylcytosine by TET1 promotes active DNA demethylation in the adult brain. Cell 145, 423e434. Guy, J., Cheval, H., Selfridge, J., Bird, A., 2011. The role of MeCP2 in the brain. Annu. Rev. Cell Dev. Biol. 27, 631e652. Guy, J., Gan, J., Selfridge, J., Cobb, S., Bird, A., 2007. Reversal of neurological defects in a mouse model of Rett syndrome. Science 315, 1143e1147. Hamby, M.E., Coskun, V., Sun, Y.E., 2008. Transcriptional regulation of neuronal differentiation: the epigenetic layer of complexity. Biochim. Biophys. Acta 1779, 432e437. He, Y.F., Li, B.Z., Li, Z., Liu, P., Wang, Y., Tang, Q., Ding, J., Jia, Y., Chen, Z., Li, L., Sun, Y., Li, X., Dai, Q., Song, C.X., Zhang, K., He, C., Xu, G.L., 2011. Tet-mediated formation of 5-carboxylcytosine and its excision by TDG in mammalian DNA. Science 333, 1303e1307. Hubel, D.H., Wiesel, T.N., 1998. Early exploration of the visual cortex. Neuron 20, 401e412. Hwang, J.Y., Aromolaran, K.A., Zukin, R.S., 2013. Epigenetic mechanisms in stroke and epilepsy. Neuropsychopharmacology 38, 167e182. Ito, S., Shen, L., Dai, Q., Wu, S.C., Collins, L.B., Swenberg, J.A., He, C., Zhang, Y., 2011. Tet proteins can convert 5-methylcytosine to 5formylcytosine and 5-carboxylcytosine. Science 333, 1300e1303. Klein, M.E., Lioy, D.T., Ma, L., Impey, S., Mandel, G., Goodman, R.H., 2007. Homeostatic regulation of MeCP2 expression by a CREB-induced microRNA. Nat. Neurosci. 10, 1513e1514. Kwok, J.B., 2010. Role of epigenetics in Alzheimer’s and Parkinson’s disease. Epigenomics 2, 671e682. Lewis, J.D., Meehan, R.R., Henzel, W.J., Maurer-Fogy, I., Jeppesen, P., Klein, F., Bird, A., 1992. Purification, sequence, and cellular localization of a novel chromosomal protein that binds to methylated DNA. Cell 69, 905e914. Lunke, S., El-Osta, A., 2009. The emerging role of epigenetic modifications and chromatin remodeling in spinal muscular atrophy. J. Neurochem. 109, 1557e1569. Lunyak, V.V., Burgess, R., Prefontaine, G.G., Nelson, C., Sze, S.H., Chenoweth, J., Schwartz, P., Pevzner, P.A., Glass, C., Mandel, G., Rosenfeld, M.G., 2002. Corepressor-dependent silencing of chromosomal regions encoding neuronal genes. Science 298, 1747e1752. Ma, D.K., Jang, M.H., Guo, J.U., Kitabatake, Y., Chang, M.L., PowAnpongkul, N., Flavell, R.A., Lu, B., Ming, G.L., Song, H., 2009. Neuronal activity-induced Gadd45b promotes epigenetic DNA demethylation and adult neurogenesis. Science 323, 1074e1077. Magill, S.T., Cambronne, X.A., Luikart, B.W., Lioy, D.T., Leighton, B.H., Westbrook, G.L., Mandel, G., Goodman, R.H., 2010. microRNA-132 regulates dendritic growth and arborization of newborn neurons in the adult hippocampus. Proc. Natl. Acad. Sci. USA 107, 20382e20387. Majdan, M., Shatz, C.J., 2006. Effects of visual experience on activitydependent gene regulation in cortex. Nat. Neurosci. 9, 650e659. Martinowich, K., Hattori, D., Wu, H., Fouse, S., He, F., Hu, Y., Fan, G., Sun, Y.E., 2003. DNA methylation-related chromatin remodeling in activity-dependent BDNF gene regulation. Science 302, 890e893.
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J. Lv et al. / Journal of Genetics and Genomics 40 (2013) 339e346
Massart, R., Mongeau, R., Lanfumey, L., 2012. Beyond the monoaminergic hypothesis: neuroplasticity and epigenetic changes in a transgenic mouse model of depression. Philos. Trans. R Soc. Lond. B Biol. Sci. 367, 2485e2494. Miller, B.H., Zeier, Z., Xi, L., Lanz, T.A., Deng, S., Strathmann, J., Willoughby, D., Kenny, P.J., Elsworth, J.D., Lawrence, M.S., Roth, R.H., Edbauer, D., Kleiman, R.J., Wahlestedt, C., 2012. MicroRNA-132 dysregulation in schizophrenia has implications for both neurodevelopment and adult brain function. Proc. Natl. Acad. Sci. USA 109, 3125e3130. Miller, C.A., Gavin, C.F., White, J.A., Parrish, R.R., Honasoge, A., Yancey, C.R., Rivera, I.M., Rubio, M.D., Rumbaugh, G., Sweatt, J.D., 2010. Cortical DNA methylation maintains remote memory. Nat. Neurosci. 13, 664e666. Miller, C.A., Sweatt, J.D., 2007. Covalent modification of DNA regulates memory formation. Neuron 53, 857e869. Moretti, P., Levenson, J.M., Battaglia, F., Atkinson, R., Teague, R., Antalffy, B., Armstrong, D., Arancio, O., Sweatt, J.D., Zoghbi, H.Y., 2006. Learning and memory and synaptic plasticity are impaired in a mouse model of Rett syndrome. J. Neurosci. 26, 319e327. Murgatroyd, C., Patchev, A.V., Wu, Y., Micale, V., Bockmuhl, Y., Fischer, D., Holsboer, F., Wotjak, C.T., Almeida, O.F., Spengler, D., 2009. Dynamic DNA methylation programs persistent adverse effects of early-life stress. Nat. Neurosci. 12, 1559e1566. Nan, X., Ng, H.H., Johnson, C.A., Laherty, C.D., Turner, B.M., Eisenman, R.N., Bird, A., 1998. Transcriptional repression by the methylCpG-binding protein MeCP2 involves a histone deacetylase complex. Nature 393, 386e389. Nijhawan, D., Honarpour, N., Wang, X., 2000. Apoptosis in neural development and disease. Annu. Rev. Neurosci. 23, 73e87. Nishioka, M., Bundo, M., Kasai, K., Iwamoto, K., 2012. DNA methylation in schizophrenia: progress and challenges of epigenetic studies. Genome Med. 4, 96. Niwa, M., Jaaro-Peled, H., Tankou, S., Seshadri, S., Hikida, T., Matsumoto, Y., Cascella, N.G., Kano, S., Ozaki, N., Nabeshima, T., Sawa, A., 2013. Adolescent stress-induced epigenetic control of dopaminergic neurons via glucocorticoids. Science 339, 335e339. Qiu, Z., Ghosh, A., 2008a. A brief history of neuronal gene expression: regulatory mechanisms and cellular consequences. Neuron 60, 449e455. Qiu, Z., Ghosh, A., 2008b. A calcium-dependent switch in a CREST-BRG1 complex regulates activity-dependent gene expression. Neuron 60, 775e787.
Qiu, Z., Sylwestrak, E.L., Lieberman, D.N., Zhang, Y., Liu, X.Y., Ghosh, A., 2012. The Rett syndrome protein MeCP2 regulates synaptic scaling. J. Neurosci. 32, 989e994. Ramocki, M.B., Peters, S.U., Tavyev, Y.J., Zhang, F., Carvalho, C.M., Schaaf, C.P., Richman, R., Fang, P., Glaze, D.G., Lupski, J.R., Zoghbi, H.Y., 2009. Autism and other neuropsychiatric symptoms are prevalent in individuals with MeCP2 duplication syndrome. Ann. Neurol. 66, 771e782. Rett, A., 1966. On a unusual brain atrophy syndrome in hyperammonemia in childhood. Wien. Med. Wochenschr 116, 723e726. Rodenas-Ruano, A., Chavez, A.E., Cossio, M.J., Castillo, P.E., Zukin, R.S., 2012. REST-dependent epigenetic remodeling promotes the developmental switch in synaptic NMDA receptors. Nat. Neurosci. 15, 1382e1390. Segal, D.S., Squire, L.R., Barondes, S.H., 1971. Cycloheximide: its effects on activity are dissociable from its effects on memory. Science 172, 82e84. Silva, A.J., Kogan, J.H., Frankland, P.W., Kida, S., 1998. CREB and memory. Annu. Rev. Neurosci. 21, 127e148. Skene, P.J., Illingworth, R.S., Webb, S., Kerr, A.R., James, K.D., Turner, D.J., Andrews, R., Bird, A.P., 2010. Neuronal MeCP2 is expressed at near histone-octamer levels and globally alters the chromatin state. Mol. Cell 37, 457e468. Squire, L.R., Barondes, S.H., 1970. Actinomycin-D: effects on memory at different times after training. Nature 225, 649e650. Suh, H., Deng, W., Gage, F.H., 2009. Signaling in adult neurogenesis. Annu. Rev. Cell Dev. Biol. 25, 253e275. Tropea, D., Kreiman, G., Lyckman, A., Mukherjee, S., Yu, H., Horng, S., Sur, M., 2006. Gene expression changes and molecular pathways mediating activity-dependent plasticity in visual cortex. Nat. Neurosci. 9, 660e668. Wu, H., Coskun, V., Tao, J., Xie, W., Ge, W., Yoshikawa, K., Li, E., Zhang, Y., Sun, Y.E., 2010. Dnmt3a-dependent nonpromoter DNA methylation facilitates transcription of neurogenic genes. Science 329, 444e448. Zhao, C., Deng, W., Gage, F.H., 2008. Mechanisms and functional implications of adult neurogenesis. Cell 132, 645e660. Zhong, X., Li, H., Chang, Q., 2012. MeCP2 phosphorylation is required for modulating synaptic scaling through mGluR5. J. Neurosci. 32, 12841e12847. Zhou, Z., Hong, E.J., Cohen, S., Zhao, W.N., Ho, H.Y., Schmidt, L., Chen, W.G., Lin, Y., Savner, E., Griffith, E.C., Hu, L., Steen, J.A., Weitz, C.J., Greenberg, M.E., 2006. Brain-specific phosphorylation of MeCP2 regulates activity-dependent Bdnf transcription, dendritic growth, and spine maturation. Neuron 52, 255e269.
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JGG REVIEW
The Epigenetic Switches for Neural Development and Psychiatric Disorders Jingwen Lv b, Yongjuan Xin a, Wenhao Zhou b,*, Zilong Qiu a,* a
Institute of Neuroscience, Shanghai Institute of Biological Sciences, Chinese Academy of Sciences, Shanghai 200031, China b Department of Neonatology, Children’s Hospital of Fudan University, Shanghai 201102, China Received 26 January 2013; revised 19 April 2013; accepted 30 April 2013 Available online 9 May 2013
ABSTRACT The most remarkable feature of the nervous system is that the development and functions of the brain are largely reshaped by postnatal experiences, in joint with genetic landscapes. The nature vs. nurture argument reminds us that both genetic and epigenetic information is indispensable for the normal function of the brain. The epigenetic regulatory mechanisms in the central nervous system have been revealed over last a decade. Moreover, the mutations of epigenetic modulator genes have been shown to be implicated in neuropsychiatric disorders, such as autism spectrum disorders. The epigenetic study has initiated in the neuroscience field for a relative short period of time. In this review, we will summarize recent discoveries about epigenetic regulation on neural development, synaptic plasticity, learning and memory, as well as neuropsychiatric disorders. Although the comprehensive view of how epigenetic regulation contributes to the function of the brain is still not completed, the notion that brain, the most complicated organ of organisms, is profoundly shaped by epigenetic switches is widely accepted. KEYWORDS: DNA methylation; Adult neurogenesis; Neural plasticity; Learning and memory; Autism; Depression
INTRODUCTION
Abbreviations: AML, acute myeloid leukemia; Avp, arginine vasopressin; BDNF, brain-derived neurotrophic factor; CBP, CREB-binding protein; CNS, central nervous system; CREB, cAMP response element-binding protein; CREST, calcium-responsive transactivator; DG, dentate gyrus; Dnmt1, DNA methyltransferase 1; Dnmt3a, DNA methyltransferase 3a; GADD45b, growth arrest and DNA-damage-inducible, beta; GluR2, glutamate receptor 2; HDAC, histone deacetylase; HDAC2, histone deacetylase 2; JAK, Janus kinase; MeCP2, methyl CpG binding protein 2; mEPSC, miniature excitatory postsynaptic current; miR-132, mircroRNA-132; MND, motor neuron diseases; PP1, protein phosphatase 1; REST, RE1-silencing transcription factor; SMA, spinal muscular atrophy; STAT, signal transducer and activator of transcription; TET1, ten-eleven translocation 1. * Corresponding authors. Tel: þ86 21 5492 1806, fax: þ86 21 5492 1735 (Z. Qiu); Tel/fax: þ86 21 6493 1003 (W. Zhou). E-mail addresses: [email protected] (W. Zhou); [email protected]. cn (Z. Qiu).
The unique feature of the central nervous system (CNS) is that the developmental process of the brain is largely regulated by experience inputs. In 1960s, Hubel and Wiesel found that deprivation of visual inputs on neonatal cats for a certain period of time would lead to the loss of vision in adulthood (Hubel and Wiesel, 1998). The following gene expression profiling studies indeed identified dramatic changes in gene expression patterns, which immediately raise the possibility that epigenetic regulatory mechanisms may play constructive roles in controlling neural development by means of regulating gene expression (Majdan and Shatz, 2006; Tropea et al., 2006). Experience-dependent gene expression events happened in the neuron are essential processes during which the neuron modifies its properties to adapt outside environments. Molecular biology studies since 1980s have identified numerous
1673-8527/$ - see front matter Copyright Ó 2013, Institute of Genetics and Developmental Biology, Chinese Academy of Sciences, and Genetics Society of China. Published by Elsevier Limited and Science Press. All rights reserved. http://dx.doi.org/10.1016/j.jgg.2013.04.007
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critical neural activity-dependent transcriptional regulators, such as cAMP responsive element-binding protein (CREB), CREB-binding protein (CBP) and calcium-responsive transactivator (CREST) (Qiu and Ghosh, 2008a, 2008b). Interestingly, CBP, one of the most critical transcriptional activators in the neuron, contains histone acetylation activity itself. Thus epigenetic studies including histone acetylation became to be one of themes in neuroscience field. Epigenetic regulatory mechanisms are involved in many aspects of formation and function of the nervous system. One of the first important steps of neural development is the generation of a variety of cell types in the brain. We will focus on discussing the epigenetic regulation during neurogenesis and gliogenesis. Next, we will discuss the epigenetic regulation of hippocampal neurogenesis in the adult animal, which plays a critical role in regulating cognitive functions. Epigenetic regulation plays a decisive role not only in neuronal fate determination, but also in neural plasticity process. The acquirement and retrieval of memory are believed to rely on epigenetic regulation of genetic switches on the genome to a large extent. Finally, in this review, we will discuss an important issue that mutations of epigenetic regulator genes are found to associate with neuropsychiatric disorders, such as autism spectrum disorders. The connection between epigenetic regulation and psychiatric disorders has attracted attentions of experts across epigenetics, neuroscience and neurology fields over the last few years. In the end, we will raise the unanswered questions and provide perspectives for the future epigenetic study in neuroscience field. EPIGENETIC CONTROL OF NEURAL DEVELOPMENT The formation of the CNS primarily depends on the genetic information stored in the genome. Nevertheless, epigenetic mechanisms via DNA methylation and histone modification are found to be essential for the expression of genes required for various steps during neural development, including neurogenesis and gliogenesis. Here, we will discuss three main events in which epigenetic regulation plays important roles discovered recently. Neurogenesis and fate determination DNA methylation and demethylation are critical switches for gene expression. The discovery that neuronal genes are repressed in non-neuronal cell by repressor element 1 silencing transcription factor (REST)-dependent DNA methylation events showed an important mechanism which neurogenesis may require (Chong et al., 1995; Lunyak et al., 2002; Ballas et al., 2005). Although the REST-dependent epigenetic switch is known to be responsible for repressing neuronal genes in non-neuronal cells, interestingly, RodenasRuano and colleagues found that the developmental expression of glutamatergic receptor subunits in the post-mitotic neurons is also regulated by REST-dependent DNA methylation (Rodenas-Ruano et al., 2012). This report provides
important insights that DNA methylation related epigenetic regulation may play a critical role in neurons during neural development as well. There are several critical steps after neurogenesis, including migration of post-mitotic neurons, dendritic and axonal morphogenesis, and initial formation of synapses. It is critical to address whether DNA methylation may be involved in these physiological processes. It is critical to address whether and how DNA methylation switches are modulated during neurogenesis. However, DNA methyltransferase 3a (Dnmt3a) is found to be required for neurogenesis in the following studies. Wu and colleagues identified an un-expected mechanism for the role of Dnmt3a in neurogenesis (Wu et al., 2010). Using genome-wide chromatin immunoprecipitation, they found that Dnmt3a mainly occupies intergenic and non-proximal promoter regions of active transcribed genes. They showed that the presence of Dnmt3a in non-proximal regions of neurogenic genes is required for their normal expression. Interestingly, the Dnmt3a-dependent methylation of non-proximal regions of neurogenic genes seems to antagonize the repression activity of a critical transcriptional repressor Polycomb, thus maintaining the active transcription of neurogenic genes (Wu et al., 2010). This novel mechanism provides important insights of epigenetic regulation of neurogenesis. The generation of glia, another critical component of the nervous system, is also regulated by DNA methylation mechanisms. The Janus kinase (JAK)-signal transducer and activator of transcription (STAT) signaling pathway have been shown to be implicated in gliogenesis. Fan and colleagues found that the genetic deletion of DNA methyltransferase 1 (Dnmt1), a critical DNA methyltransferase in the nervous system, leads to premature glia differentiation. They found that methylation of certain JAK-STAT pathway genes is required for controlling gliogenesis in the correct timing. Loss of Dnmt1 and DNA methylation control therefore leads to abnormal expression of gliogenic genes (Fan et al., 2005). Thus, epigenetic regulations involving DNA methylation are found to be crucial for the fate determination of neuron and glia in the nervous system (Hamby et al., 2008; Coskun et al., 2012). An important question that needs to be answered next is whether and how epigenetic switches during neurogenesis and gliogenesis could be regulated by experience-dependent outside inputs. Would experience input received by organisms be able to influence the building landscape of the nervous system? Given the current discoveries that epigenetic switches are deeply controlled by environmental stimulus, we would like to propose the hypothesis that the generation of neuron and glia in the nervous system may also be regulated by the environment inputs via epigenetic regulatory mechanisms. Adult hippocampal neurogenesis One of the interesting properties of the CNS is that new neurons could be continuously generated throughout the adulthood, which is called adult neurogenesis. There are two regions in the brain where adult neurogenesis occurs,
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i.e., dentate gyrus (DG) of the hippocampus and olfactory bulb (Zhao et al., 2008; Suh et al., 2009; Aimone et al., 2011). Neuronal activity has been found to be associated with neurogenesis in the DG previously. Ma and colleagues found that the neural activity would lead to rapid expression of a gene called growth arrest and DNA-damage-inducible 45b (Gadd45b) (Ma et al., 2009). Importantly, they found that Gadd45b is required for the activity-induced proliferation of neural progenitor cells and activity-induced gene expression in the DG. It turns out that Gadd45b is required for the demethylation of promoters of critical genes responsible for new-born neuron development, such as brain-derived neurotrophic factor (BDNF). The electric stimulus that would enhance neurogenesis in DG has less effects on Gadd45b knockout mice. This critical study identified an important epigenetic regulator that plays a critical role in regulating adult neurogenesis in response to environment stimulus (Faigle and Song, 2012). In another report, the same research group used chromatin immunoprecipitation combined with microarray methods to measure the global change of DNA methylation in DG upon neural activity. Surprisingly, they found around 1.4% CpG islands in DG neurons are actively methylated and demethylated upon electric shock, which is higher than previous thought (Guo et al., 2011). This study provides a more comprehensive view about DNA methylation profiling happened in genomes of post-mitotic neurons and further suggests that the methylation status of post-mitotic neurons is not as static as previously hypothesized. More interestingly, electric shock equipment used in these studies has therapeutic effects to human patients with depression and other psychiatric disorders, which raises the possibility that epigenetic regulatory mechanisms may play important role in pathophysiology of neuropsychiatric disorders. Guo and coworkers showed that the expression of Dnmt3a is up-regulated by neural activity caused by electric shock equipment (Guo et al., 2011). However, in another study, Miller and colleagues found that Dnmt3a is regulated by a neuronal-specific microRNAemiR-132, which is up-regulated by neural activity (Klein et al., 2007; Magill et al., 2010; Miller et al., 2012). These controversial findings suggest that the regulatory mechanisms for the expression of Dnmt3a in neuron may include multiple mechanisms. Thus, it will be of great interest to elucidate the molecular mechanisms of controlling Dnmt3a expression in post-mitotic neurons (Fig. 1). The DNA active demethylation mechanisms including teneleven translocation (Tet)-dependent 5 mC hydroxylation have been revealed recently (He et al., 2011; Ito et al., 2011). Indeed, Guo and colleagues also found that ten-eleven translocation 1 (Tet1) plays a critical role in mediating DNA demethylation process in post-mitotic neurons in hippocampal DG region upon neural activity caused by electric shock (Guo et al., 2011a, 2011b). They showed that Tet1 is required for neural activity-induced DNA demethylation and therefore activity-dependent gene expression. But that leaves us some interesting questions: What is the switch to turn on the Tet1 activity upon neural activity? Whether Tet1 expression level is up-regulated by neural activity? Or is Tet1 modified by
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post-translational modifications such as phosphorylation? These questions are critical for us to further understand how environment stimuli trigger DNA active demethylation process in the nervous system. Neuronal apoptosis and neurodegenerative disorders The massive neuronal apoptosis takes place during neural development (Nijhawan et al., 2000). Moreover, abnormal neuronal death is closely associated with neurodegenerative disorders, such as Alzheimer’s and Parkinson’s disease (Kwok, 2010; Hwang et al., 2013). Thus, the common epigenetic regulatory mechanisms identified in other systems are most likely shared in the nervous system. Recently, the studies of motor neuron diseases (MND) and spinal muscular atrophy (SMA) strongly suggest that the abnormal death of motor neurons may lead to severe disorders (Lunke and El-Osta, 2009). An interesting study by Chestnut and colleagues identified a role for DNA methylation in motor neuron death (Chestnut et al., 2011). They found that introduction of Dnmt3a could induce neuronal cell death using cultured motor neuron in vitro. Therefore, inhibition of DNA methylation pharmacologically could promote motor neuron survival under apoptotic stimulus. This report is of special benefits to current mechanisms and potential therapeutic studies about MND. Whether manipulations of DNA methylation would have effects on treatment of MND? DNA methylation blockers have been used for certain cancer like acute myeloid leukemia (AML). Whether or not the similar therapy may have effects on MND would have immediate clinical significance. EPIGENETIC CONTROL OF SYNAPTIC PLASTICITY The molecular mechanisms for learning and memory include proper gene expression induced by environmental stimuli. The learning induced gene expression and protein synthesis are required for memory achievement and retrieval (Squire and Barondes, 1970; Segal et al., 1971). Therefore, learning-induced epigenetic regulatory mechanisms are inevitably involved in the formation, store and retrieval of memory. Indeed, studies from last few years have accumulated compelling evidences that both DNA methylation and histone acetylation play pivotal roles in controlling learning and memory. DNA methylation in learning and memory Genetic studies by Feng and colleagues showed that both Dnmt1 and Dnmt3a are required for learning and memory, as well as hippocampal synaptic plasticity (Feng et al., 2010). This is a critical study showing that DNA methylation events in the mature nervous system are critical for the normal function. They used genetics methods to knockout Dnmt1 and Dnmt3a in the post-mitotic forebrain neurons of mouse. They found that only deletion of both Dnmt1 and Dnmt3a could lead
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Fig. 1. Signaling pathway for regulating Dnmt3a expression in post-mitotic neurons. Calcium influx in neurons activates CaMKIV, which actives CREB and then stimulates the expression of miR-132. The up-regulation of miR-132 will target Dnmt3a mRNA and result in down-regulation of Dnmt3a protein. CaMKIV, calmodulin-dependent kinase IV; CREB, cAMP responsive element-binding protein.
to deficiency in learning and memory, suggesting that the DNA methylation mechanisms in mature neurons required both Dnmt1 and Dnmt3. This finding is of particular interest since Dnmt1 was found to be critical for maintenance of DNA methylation and might not be required for active DNA methylation. Thus, there are unknown mechanisms in the nervous system that are responsible for DNA methylation in response to learning-induced activity. Interestingly, the DNMT protein level was found to be upregulated during the fear conditioning (Miller and Sweatt, 2007). A memory suppressor gene protein phosphatase 1 (PP1) was repressed by rapid DNA methylation mechanisms. It is important to address whether the enhanced DNA methylation associated with fear conditioning is global across the genome or only happens in certain regions. Miller and colleagues reported that calcineurin, another critical gene involved in learning and memory, is also regulated by hippocampus-dependent associative learning stimulus (Miller et al., 2010). Strikingly, they showed that pharmacological blockade of DNA methylation one month after memory acquirement is still able to disrupt the retrieval of remote memory. These results strongly suggest that DNA methylation event indeed plays a critical role in regulating memory formation and retrieval (Day and Sweatt, 2010, 2011). However, considering the complexity of neural circuitry involved in learning and memory, it is important to address the molecular mechanisms underlying DNA methylation regulated memory formation and retrieval. Several critical questions remain to be answered, such as whether learning-induced DNA methylation is a global effect, in which neuronal populations learninginduced DNA methylation happens, and how neural activity turned on DNA methylation machinery specifically.
Histone modification in learning and memory Another critical epigenetic regulation is modification of histone proteins. There are several important publications over the last few years about the role of histone modification in learning and memory. Initially, Fischer and colleagues used histone deacetylase (HDAC) inhibitors to study whether blocking HDAC may alleviate the cognitive defects in a mouse model of Alzheimer’s diseases (Fischer et al., 2007). They found that HDAC inhibitors exhibited positive effects on mice with cognitive deficit. Moreover, they found that HDAC inhibitors also have effects on wild type animals and showed cognitive enhancement of wild type mice being given HDAC inhibitors. In the following studies, Guan and colleagues found that histone deacetylase 2 (HDAC2), one of the major histone deacetylase, plays a negative role in regulating learning and memory. The gain- and loss-of-function experiments showed that HDAC2 is a critical modulator for memory formation and synaptic plasticity (Guan et al., 2009). Still, the unanswered questions that need to be addressed in the further studies include, but not limited to, the mechanism of HDAC2regulating synaptic plasticity, whether HDAC2 contributes to particular neural circuitry and how histone acetylation interplays with DNA methylation in the memory formation and synaptic plasticity. The same research group went on to show that Sirt1, a histone acetylase, plays a negative role in memory formation (Gao et al., 2010). Interestingly, they found that Sirt1 promotes the expression of a critical micoRNAemiR-134, which targets the critical activity-dependent transcriptional factoreCREB essential for learning and memory (Silva et al., 1998). Thus, Sirt1 plays a negative role in memory formation by a Sirt1-
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miR-134-CREB signaling pathway. These results deliver important message that histone acetylation plays a dynamic role in controlling memory formation and synaptic plasticity. However, it is still too early to draw the conclusion about how histone acetylation or deacetylation plays certain roles on learning and memory without knowing whether the effects of HDAC2 and Sirt1 are general or specific to particular genes (Graff and Tsai, 2013). NEUROPSYCHIATRIC DISORDERS Since the wide involvement of epigenetic regulation in many aspects of neural development and plasticity, it is important to ask whether genetic mutations associated with epigenetic regulators may be linked to disorders of the nervous system. Recently, accumulated evidences have implicated the roles of the epigenetic factors in neuropsychiatric disorders. Here, we will particularly focus on two critical neuropsychiatric disorders, autism spectrum disorders and major depression disorders. MeCP2 and autism spectrum disorders Autism spectrum disorders are a group of neurodevelopmental disorders, characterized by deficiency in social communication and language development. The studies of Rett syndrome, one of severe forms of autism spectrum disorders, provide important insights about epigenetic regulation of autism spectrum disorders. The Rett syndrome was characterized in 1960s by Dr. Rett (1966). This developmental delay disorder is usually associated with girls and the main genetic cause of Rett syndrome was found to be the dysfunction of a single gene methyl CpG binding protein 2 (MeCP2) identified in 1999 (Amir et al., 1999). MeCP2 gene was initially cloned to encode a methyl CpG binding protein, which plays a critical role in repressing gene expression by recruiting HDAC complex (Lewis et al., 1992; Nan et al., 1998). More interestingly, the duplications of genomic locus including mecp2 have been found in autism patients (Ramocki et al., 2009). Thus both loss- and gain-of-function of MeCP2 could lead to defects in neural development and yield psychiatric symptoms (Chahrour and Zoghbi, 2007; Guy et al., 2011). The identification of MeCP2 as the genetic cause for Rett syndrome immediately attracted wide interests across many fields including epigenetics, neuroscience and psychiatrics. What role may MeCP2 play as an epigenetic regulator in the pathology of autism spectrum disorders? Two studies in 2003 provide important insights of the role of MeCP2 in regulating gene expression in the nervous system (Chen et al., 2003; Martinowich et al., 2003). Both groups found that MeCP2 binds to the CpG islands on the promoter of BDNF gene, an important neurotrophic factor, and the activity of neuron rapidly induces the dissociation between MeCP2 and BDNF promoter, which allows the expression of BDNF in response to neural activity. Calcium influx induced by neural activity lead to the phosphorylation of MeCP2 on Serine 421 site, which is
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required for the release of MeCP2 from BDNF promoter. Zhou and coworkers found that the phosphorylation of Serine 421 site of MeCP2 plays a critical role in regulating the development of hippocampal dendritic spines, the mature form of excitatory synapses (Zhou et al., 2006). More functional studies showed that MeCP2 in the neuron is responsible for modulating global state of the chromatin (Skene et al., 2010). Qiu and colleagues found that MeCP2 represses the expression of glutamate receptor 2 (GluR2), a critical subunit of glutamatergic receptors in response to neural activity (Qiu et al., 2012). The repression of GluR2 by MeCP2 upon neural activity is a homeostatic response in the neuron. When neurons are activated by neurotransmitters such as glutamate, the fire rate of neuron will increase, which leads to the MeCP2-dependent repression of GluR2. Loss of GluR2 in turn down-regulates the strength of the synapse and activity of the neuron. This negative feedback is essential for maintenance of neural network. Importantly, Qiu and coworkers showed that this homeostatic response is disrupted in mecp2 knockout mouse, which is the mouse model for Rett syndrome (Qiu et al., 2012). Following studies also identified the key role of MeCP2 in other form of synaptic homeostatic plasticity (Zhong et al., 2012; Blackman et al., 2012). These findings provide important insights about the epigenetic regulation mediated by MeCP2, which is critical for the stability control of the neural network and further suggests that the disruption of neural network stability may be the key contribution factor of autism spectrum disorder pathophysiology (Fig. 2). Researchers have made various animal models for studying the role of MeCP2 in neural development and plasticity. Severe cognitive defects are found in mecp2 knockout mice, suggesting that the mecp2 null mouse serves as a valuable model for mimicking Rett syndrome (Moretti et al., 2006). Since the developmental plasticity of the brain is gradually decreasing during adulthood, the critical question from clinical perspectives is whether the nervous system without mecp2 would be still able to recover if MeCP2 is re-introduced after infant stage, when Rett syndrome is usually diagnosed. Guy and colleagues used sophisticated mouse genetics methods to show that reintroduction of MeCP2 into mecp2 null mouse during adulthood lead to full recovery of the mice with severe phenotypes (Guy et al., 2007). This study is particularly important for the therapeutic study of Rett syndrome and also raises interesting questions how the adult brain still fully recovers after passing early developmental stages. Moreover, it is suggested that epigenetic regulation may play an even more important role in therapeutic efforts for psychiatric disorders, given the fact that epigenetic manipulations could work during adulthood. Experience-dependent epigenetic modulation and depression It is worth notice that the depression symptoms are found to associate with family members of autism patients with MeCP2
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Fig. 2. Homeostatic signaling pathway mediated by MeCP2. When neuron receives stimulus, intracellular CaMKIV-mediated signaling pathway is activated, which results in the activation of CREST-containing transcriptional complex and promotes the expression of MeCP2. MeCP2 in turn represses the expression of GluR2 which leads to the inhibition of mEPSC and homeostatic regulation of neuronal excitability. CaMKIV, calmodulin-dependent kinase IV; CREST, calcium-responsive transactivator; MeCP2, methyl CpG binding protein 2; GluR2, glutamate receptor 2; mEPSC, miniature excitatory postsynaptic current.
genomic duplications (Ramocki et al., 2009). Whether MeCP2 is directly involved in depression disorders is an important question needs to be addressed. Hutchinson and colleagues found that antidepressant administration induces rapid phosphorylation of MeCP2 on Serine 421 site in lateral habenula region in the brain and the mice carrying the MeCP2 phosphorylation deficient mutant S421A appear to have more depressive phenotypes in force swimming and tail suspension tests as compared to wild type mice. Thus, this study indicates that phosphorylation of MeCP2 on Serine 421 site plays an endogenous role in the response of depressive stimulus and the physiological responses of antidepressants. Whether epigenetic modulations may play roles in other forms of stress response? Murgatroyd and colleagues found that early-life stress in mice led to abnormal level of corticosterone and behavior alternations associated with depression (Murgatroyd et al., 2009). Interestingly, they found that the activity-dependent expression of arginine vasopressin (Avp), a critical hormone for stress response, was regulated by MeCP2 and therefore early-life stress induced abnormal regulation of Avp expression mediated by MeCP2. This finding showed that epigenetic regulations are critical for prolonged responses of stress stimuli. Whether DNA methylation and histone modifications would be involved in epigenetic modulations for stress response in either acute or prolonged period would be interesting questions to address. Considering the different time scales of DNA methylation and histone modifications, they may play distinct roles in regulating stress responses (Massart et al., 2012; Nishioka et al., 2012).
CONCLUDING REMARKS AND PERSPECTIVES Taken together, it is recognized that epigenetic regulator mechanisms are significant switches for the neural development and plasticity, as well as disorders. Regarding to further studies, it is important that biochemical discovery could be more closely linked to physiological relevance. Moreover, it is essential to realize that the brain is a complicated organ composed by billions of cells and even more neural connections. Therefore, the role a single gene may play must be interpreted under the scape of various cell types and different neural circuitries. However, if animal carrying a single gene mutation, which is involved in epigenetic regulation, appears to have cognitive effects, but without knowing which neural circuitry is actually affected, the knowledge we learn will be very limited. The available mouse genetics methods offer good tools to manipulate specific neural circuitry with precise timing control. Thus the further study must take advantage of the progress in mouse genetics methods to address the role of epigenetic regulators in neural development and plasticity. Moreover, we hope that the specific feature of epigenetic regulation should not be omitted. Epigenetic control may serve as the bridge of connecting environmental inputs with genetic switches and play a central role in mediating the prolonged physiological responses of organisms. Finally, there are two surprising reports published very recently showing that stress from early age could lead to prolonged behavioral consequences by epigenetic control of the gene expression of dopamine synthesis enzyme via glucocorticoid signaling
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pathway (Barik et al., 2013; Niwa et al., 2013). This will shed new lights on the epigenetic research in neuroscience field and provide new routes through which mechanistic studies on complicated physiological responses of organisms by epigenetic regulation could be performed. ACKNOWLEDGEMENTS This work was supported by the grant from the National Natural Science Foundation of China (the Fostering Project of the Major Research) (No. 91232712). REFERENCES Aimone, J.B., Deng, W., Gage, F.H., 2011. Resolving new memories: a critical look at the dentate gyrus, adult neurogenesis, and pattern separation. Neuron 70, 589e596. Amir, R.E., Van den Veyver, I.B., Wan, M., Tran, C.Q., Francke, U., Zoghbi, H.Y., 1999. Rett syndrome is caused by mutations in X-linked MECP2, encoding methyl-CpG-binding protein 2. Nat. Genet. 23, 185e188. Ballas, N., Grunseich, C., Lu, D.D., Speh, J.C., Mandel, G., 2005. REST and its corepressors mediate plasticity of neuronal gene chromatin throughout neurogenesis. Cell 121, 645e657. Barik, J., Marti, F., Morel, C., Fernandez, S.P., Lanteri, C., Godeheu, G., Tassin, J.P., Mombereau, C., Faure, P., Tronche, F., 2013. Chronic stress triggers social aversion via glucocorticoid receptor in dopaminoceptive neurons. Science 339, 332e335. Blackman, M.P., Djukic, B., Nelson, S.B., Turrigiano, G.G., 2012. A critical and cell-autonomous role for MeCP2 in synaptic scaling up. J. Neurosci. 32, 13529e13536. Chahrour, M., Zoghbi, H.Y., 2007. The story of Rett syndrome: from clinic to neurobiology. Neuron 56, 422e437. Chen, W.G., Chang, Q., Lin, Y., Meissner, A., West, A.E., Griffith, E.C., Jaenisch, R., Greenberg, M.E., 2003. Derepression of BDNF transcription involves calcium-dependent phosphorylation of MeCP2. Science 302, 885e889. Chestnut, B.A., Chang, Q., Price, A., Lesuisse, C., Wong, M., Martin, L.J., 2011. Epigenetic regulation of motor neuron cell death through DNA methylation. J. Neurosci. 31, 16619e16636. Chong, J.A., Tapia-Ramirez, J., Kim, S., Toledo-Aral, J.J., Zheng, Y., Boutros, M.C., Altshuller, Y.M., Frohman, M.A., Kraner, S.D., Mandel, G., 1995. REST: a mammalian silencer protein that restricts sodium channel gene expression to neurons. Cell 80, 949e957. Coskun, V., Tsoa, R., Sun, Y.E., 2012. Epigenetic regulation of stem cells differentiating along the neural lineage. Curr. Opin. Neurobiol. 22, 762e767. Day, J.J., Sweatt, J.D., 2010. DNA methylation and memory formation. Nat. Neurosci. 13, 1319e1323. Day, J.J., Sweatt, J.D., 2011. Epigenetic mechanisms in cognition. Neuron 70, 813e829. Faigle, R., Song, H., 2012. Signaling mechanisms regulating adult neural stem cells and neurogenesis. Biochim. Biophys. Acta 1830, 2435e2448. Fan, G., Martinowich, K., Chin, M.H., He, F., Fouse, S.D., Hutnick, L., Hattori, D., Ge, W., Shen, Y., Wu, H., Ten, H.J., Shuai, K., Sun, Y.E., 2005. DNA methylation controls the timing of astrogliogenesis through regulation of JAK-STAT signaling. Development 132, 3345e3356. Feng, J., Zhou, Y., Campbell, S.L., Le, T., Li, E., Sweatt, J.D., Silva, A.J., Fan, G., 2010. Dnmt1 and Dnmt3a maintain DNA methylation and regulate synaptic function in adult forebrain neurons. Nat. Neurosci. 13, 423e430. Fischer, A., Sananbenesi, F., Wang, X., Dobbin, M., Tsai, L.H., 2007. Recovery of learning and memory is associated with chromatin remodelling. Nature 447, 178e182.
345
Gao, J., Wang, W.Y., Mao, Y.W., Graff, J., Guan, J.S., Pan, L., Mak, G., Kim, D., Su, S.C., Tsai, L.H., 2010. A novel pathway regulates memory and plasticity via SIRT1 and miR-134. Nature 466, 1105e1109. Graff, J., Tsai, L.H., 2013. The potential of HDAC inhibitors as cognitive enhancers. Annu. Rev. Pharmacol. Toxicol. 53, 311e330. Guan, J.S., Haggarty, S.J., Giacometti, E., Dannenberg, J.H., Joseph, N., Gao, J., Nieland, T.J., Zhou, Y., Wang, X., Mazitschek, R., Bradner, J.E., DePinho, R.A., Jaenisch, R., Tsai, L.H., 2009. HDAC2 negatively regulates memory formation and synaptic plasticity. Nature 459, 55e60. Guo, J.U., Ma, D.K., Mo, H., Ball, M.P., Jang, M.H., Bonaguidi, M.A., Balazer, J.A., Eaves, H.L., Xie, B., Ford, E., Zhang, K., Ming, G.L., Gao, Y., Song, H., 2011. Neuronal activity modifies the DNA methylation landscape in the adult brain. Nat. Neurosci. 14, 1345e1351. Guo, J.U., Su, Y., Zhong, C., Ming, G.L., Song, H., 2011a. Emerging roles of TET proteins and 5-hydroxymethylcytosines in active DNA demethylation and beyond. Cell Cycle 10, 2662e2668. Guo, J.U., Su, Y., Zhong, C., Ming, G.L., Song, H., 2011b. Hydroxylation of 5methylcytosine by TET1 promotes active DNA demethylation in the adult brain. Cell 145, 423e434. Guy, J., Cheval, H., Selfridge, J., Bird, A., 2011. The role of MeCP2 in the brain. Annu. Rev. Cell Dev. Biol. 27, 631e652. Guy, J., Gan, J., Selfridge, J., Cobb, S., Bird, A., 2007. Reversal of neurological defects in a mouse model of Rett syndrome. Science 315, 1143e1147. Hamby, M.E., Coskun, V., Sun, Y.E., 2008. Transcriptional regulation of neuronal differentiation: the epigenetic layer of complexity. Biochim. Biophys. Acta 1779, 432e437. He, Y.F., Li, B.Z., Li, Z., Liu, P., Wang, Y., Tang, Q., Ding, J., Jia, Y., Chen, Z., Li, L., Sun, Y., Li, X., Dai, Q., Song, C.X., Zhang, K., He, C., Xu, G.L., 2011. Tet-mediated formation of 5-carboxylcytosine and its excision by TDG in mammalian DNA. Science 333, 1303e1307. Hubel, D.H., Wiesel, T.N., 1998. Early exploration of the visual cortex. Neuron 20, 401e412. Hwang, J.Y., Aromolaran, K.A., Zukin, R.S., 2013. Epigenetic mechanisms in stroke and epilepsy. Neuropsychopharmacology 38, 167e182. Ito, S., Shen, L., Dai, Q., Wu, S.C., Collins, L.B., Swenberg, J.A., He, C., Zhang, Y., 2011. Tet proteins can convert 5-methylcytosine to 5formylcytosine and 5-carboxylcytosine. Science 333, 1300e1303. Klein, M.E., Lioy, D.T., Ma, L., Impey, S., Mandel, G., Goodman, R.H., 2007. Homeostatic regulation of MeCP2 expression by a CREB-induced microRNA. Nat. Neurosci. 10, 1513e1514. Kwok, J.B., 2010. Role of epigenetics in Alzheimer’s and Parkinson’s disease. Epigenomics 2, 671e682. Lewis, J.D., Meehan, R.R., Henzel, W.J., Maurer-Fogy, I., Jeppesen, P., Klein, F., Bird, A., 1992. Purification, sequence, and cellular localization of a novel chromosomal protein that binds to methylated DNA. Cell 69, 905e914. Lunke, S., El-Osta, A., 2009. The emerging role of epigenetic modifications and chromatin remodeling in spinal muscular atrophy. J. Neurochem. 109, 1557e1569. Lunyak, V.V., Burgess, R., Prefontaine, G.G., Nelson, C., Sze, S.H., Chenoweth, J., Schwartz, P., Pevzner, P.A., Glass, C., Mandel, G., Rosenfeld, M.G., 2002. Corepressor-dependent silencing of chromosomal regions encoding neuronal genes. Science 298, 1747e1752. Ma, D.K., Jang, M.H., Guo, J.U., Kitabatake, Y., Chang, M.L., PowAnpongkul, N., Flavell, R.A., Lu, B., Ming, G.L., Song, H., 2009. Neuronal activity-induced Gadd45b promotes epigenetic DNA demethylation and adult neurogenesis. Science 323, 1074e1077. Magill, S.T., Cambronne, X.A., Luikart, B.W., Lioy, D.T., Leighton, B.H., Westbrook, G.L., Mandel, G., Goodman, R.H., 2010. microRNA-132 regulates dendritic growth and arborization of newborn neurons in the adult hippocampus. Proc. Natl. Acad. Sci. USA 107, 20382e20387. Majdan, M., Shatz, C.J., 2006. Effects of visual experience on activitydependent gene regulation in cortex. Nat. Neurosci. 9, 650e659. Martinowich, K., Hattori, D., Wu, H., Fouse, S., He, F., Hu, Y., Fan, G., Sun, Y.E., 2003. DNA methylation-related chromatin remodeling in activity-dependent BDNF gene regulation. Science 302, 890e893.
346
J. Lv et al. / Journal of Genetics and Genomics 40 (2013) 339e346
Massart, R., Mongeau, R., Lanfumey, L., 2012. Beyond the monoaminergic hypothesis: neuroplasticity and epigenetic changes in a transgenic mouse model of depression. Philos. Trans. R Soc. Lond. B Biol. Sci. 367, 2485e2494. Miller, B.H., Zeier, Z., Xi, L., Lanz, T.A., Deng, S., Strathmann, J., Willoughby, D., Kenny, P.J., Elsworth, J.D., Lawrence, M.S., Roth, R.H., Edbauer, D., Kleiman, R.J., Wahlestedt, C., 2012. MicroRNA-132 dysregulation in schizophrenia has implications for both neurodevelopment and adult brain function. Proc. Natl. Acad. Sci. USA 109, 3125e3130. Miller, C.A., Gavin, C.F., White, J.A., Parrish, R.R., Honasoge, A., Yancey, C.R., Rivera, I.M., Rubio, M.D., Rumbaugh, G., Sweatt, J.D., 2010. Cortical DNA methylation maintains remote memory. Nat. Neurosci. 13, 664e666. Miller, C.A., Sweatt, J.D., 2007. Covalent modification of DNA regulates memory formation. Neuron 53, 857e869. Moretti, P., Levenson, J.M., Battaglia, F., Atkinson, R., Teague, R., Antalffy, B., Armstrong, D., Arancio, O., Sweatt, J.D., Zoghbi, H.Y., 2006. Learning and memory and synaptic plasticity are impaired in a mouse model of Rett syndrome. J. Neurosci. 26, 319e327. Murgatroyd, C., Patchev, A.V., Wu, Y., Micale, V., Bockmuhl, Y., Fischer, D., Holsboer, F., Wotjak, C.T., Almeida, O.F., Spengler, D., 2009. Dynamic DNA methylation programs persistent adverse effects of early-life stress. Nat. Neurosci. 12, 1559e1566. Nan, X., Ng, H.H., Johnson, C.A., Laherty, C.D., Turner, B.M., Eisenman, R.N., Bird, A., 1998. Transcriptional repression by the methylCpG-binding protein MeCP2 involves a histone deacetylase complex. Nature 393, 386e389. Nijhawan, D., Honarpour, N., Wang, X., 2000. Apoptosis in neural development and disease. Annu. Rev. Neurosci. 23, 73e87. Nishioka, M., Bundo, M., Kasai, K., Iwamoto, K., 2012. DNA methylation in schizophrenia: progress and challenges of epigenetic studies. Genome Med. 4, 96. Niwa, M., Jaaro-Peled, H., Tankou, S., Seshadri, S., Hikida, T., Matsumoto, Y., Cascella, N.G., Kano, S., Ozaki, N., Nabeshima, T., Sawa, A., 2013. Adolescent stress-induced epigenetic control of dopaminergic neurons via glucocorticoids. Science 339, 335e339. Qiu, Z., Ghosh, A., 2008a. A brief history of neuronal gene expression: regulatory mechanisms and cellular consequences. Neuron 60, 449e455. Qiu, Z., Ghosh, A., 2008b. A calcium-dependent switch in a CREST-BRG1 complex regulates activity-dependent gene expression. Neuron 60, 775e787.
Qiu, Z., Sylwestrak, E.L., Lieberman, D.N., Zhang, Y., Liu, X.Y., Ghosh, A., 2012. The Rett syndrome protein MeCP2 regulates synaptic scaling. J. Neurosci. 32, 989e994. Ramocki, M.B., Peters, S.U., Tavyev, Y.J., Zhang, F., Carvalho, C.M., Schaaf, C.P., Richman, R., Fang, P., Glaze, D.G., Lupski, J.R., Zoghbi, H.Y., 2009. Autism and other neuropsychiatric symptoms are prevalent in individuals with MeCP2 duplication syndrome. Ann. Neurol. 66, 771e782. Rett, A., 1966. On a unusual brain atrophy syndrome in hyperammonemia in childhood. Wien. Med. Wochenschr 116, 723e726. Rodenas-Ruano, A., Chavez, A.E., Cossio, M.J., Castillo, P.E., Zukin, R.S., 2012. REST-dependent epigenetic remodeling promotes the developmental switch in synaptic NMDA receptors. Nat. Neurosci. 15, 1382e1390. Segal, D.S., Squire, L.R., Barondes, S.H., 1971. Cycloheximide: its effects on activity are dissociable from its effects on memory. Science 172, 82e84. Silva, A.J., Kogan, J.H., Frankland, P.W., Kida, S., 1998. CREB and memory. Annu. Rev. Neurosci. 21, 127e148. Skene, P.J., Illingworth, R.S., Webb, S., Kerr, A.R., James, K.D., Turner, D.J., Andrews, R., Bird, A.P., 2010. Neuronal MeCP2 is expressed at near histone-octamer levels and globally alters the chromatin state. Mol. Cell 37, 457e468. Squire, L.R., Barondes, S.H., 1970. Actinomycin-D: effects on memory at different times after training. Nature 225, 649e650. Suh, H., Deng, W., Gage, F.H., 2009. Signaling in adult neurogenesis. Annu. Rev. Cell Dev. Biol. 25, 253e275. Tropea, D., Kreiman, G., Lyckman, A., Mukherjee, S., Yu, H., Horng, S., Sur, M., 2006. Gene expression changes and molecular pathways mediating activity-dependent plasticity in visual cortex. Nat. Neurosci. 9, 660e668. Wu, H., Coskun, V., Tao, J., Xie, W., Ge, W., Yoshikawa, K., Li, E., Zhang, Y., Sun, Y.E., 2010. Dnmt3a-dependent nonpromoter DNA methylation facilitates transcription of neurogenic genes. Science 329, 444e448. Zhao, C., Deng, W., Gage, F.H., 2008. Mechanisms and functional implications of adult neurogenesis. Cell 132, 645e660. Zhong, X., Li, H., Chang, Q., 2012. MeCP2 phosphorylation is required for modulating synaptic scaling through mGluR5. J. Neurosci. 32, 12841e12847. Zhou, Z., Hong, E.J., Cohen, S., Zhao, W.N., Ho, H.Y., Schmidt, L., Chen, W.G., Lin, Y., Savner, E., Griffith, E.C., Hu, L., Steen, J.A., Weitz, C.J., Greenberg, M.E., 2006. Brain-specific phosphorylation of MeCP2 regulates activity-dependent Bdnf transcription, dendritic growth, and spine maturation. Neuron 52, 255e269.