TET1 Controls CNS 5-Methylcytosine Hydroxylation, Active DNA Demethylation, Gene Transcription, and Memory Formation

Kaas, Garrett A.; Zhong, Chun; Eason, Dawn E.; Ross, Daniel L.; Vachhani, Raj V.; Ming, Guo Li; King, Jennifer R.; Song, Hongjun; Sweatt, J. David

doi:10.1016/j.neuron.2013.08.032

Cited by 371 publications

(388 citation statements)

References 38 publications

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“…For example, the intragenic accumulation of 5-hmC induced by extinction training may be associated with Tet3, whereas the accumulation of 5-hmC within distal regulatory elements and proximal promoters may be associated with the recruitment of Tet1 after fear learning. Indeed, Tet1 accumulation in promoter regions after hippocampal-dependent contextual fear conditioning has previously been demonstrated (28). The accumulation of these DNA base modifications may have different effects depending on whether they occur at single bases within key binding motifs, which would suggest a role in regulating transcription factor activity, and potentially alternative splicing, or if they are more broadly distributed, the pattern of accumulation may be indicative of a role in the regulation of DNA structure or chromatin looping (39).…”

Section: Discussionmentioning

confidence: 96%

“…Recent evidence indicates that Tet1 promotes active DNA demethylation in the adult hippocampus (8) and that the accumulation of 5-hmC and associated effects on gene expression are involved in adult neurogenesis, spatial learning, and the extinction of contextual fear (27)(28)(29). In contrast, Tet3 is highly expressed in the adult cortex (30), although its function with respect to fear extinction memory has yet to be determined.…”

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confidence: 99%

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Neocortical Tet3-mediated accumulation of 5-hydroxymethylcytosine promotes rapid behavioral adaptation

Wei

Zhao

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

166

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5-hydroxymethylcytosine (5-hmC) is a novel DNA modification that is highly enriched in the adult brain and dynamically regulated by neural activity. 5-hmC accumulates across the lifespan; however, the functional relevance of this change in 5-hmC and whether it is necessary for behavioral adaptation have not been fully elucidated. Moreover, although the ten-eleven translocation (Tet) family of enzymes is known to be essential for converting methylated DNA to 5-hmC, the role of individual Tet proteins in the adult cortex remains unclear. Using 5-hmC capture together with high-throughput DNA sequencing on individual mice, we show that fear extinction, an important form of reversal learning, leads to a dramatic genome-wide redistribution of 5-hmC within the infralimbic prefrontal cortex. Moreover, extinction learning-induced Tet3-mediated accumulation of 5-hmC is associated with the establishment of epigenetic states that promote gene expression and rapid behavioral adaptation.E pigenetic mechanisms are critically involved in the regulation of gene expression underlying learning and memory (1). Dynamic variation in the accumulation of a particular epigenetic mark, 5-methycytosine (5-mC), has emerged as a key factor in experience-dependent plasticity and the formation of fearrelated memory (2). However, 5-mC is not the only covalent modification of DNA in eukaryotes, as methylated cytosine guanine (CpG) dinucleotides can be successively oxidized and converted to 5-hydroxymethylcytosine (5-hmC), 5-formylcytosine (5-fC), and 5-carboxylcytosine by the Tet family of DNA dioxygenases (3, 4). Although little is known about the functional relevance of 5-fC and 5-carboxylcytosine (5, 6), an understanding of 5-hmC is starting to emerge. 5-hmC is highly enriched in the adult brain (7), dynamically regulated by neural activity (8), and accumulates across the lifespan (9). This epigenetic mark is critically involved in neuronal differentiation and in the reprogramming of pluripotent stem cells (10), and rather than being an intermediate state of active DNA demethylation, 5-hmC can be either dynamic or stable (8, 10). Unlike its repressive cousin, 5-mC, which is primarily found along CpG-rich gene promoters, 5-hmC is enriched within gene bodies and at intronexon boundaries of synaptic plasticity-related genes, as well as within distal cis-regulatory elements, which together point to an important role for 5-hmC in coordinating transcriptional activity (11-13). Thus, it is evident that the relationship between this particular covalent modification of DNA and gene expression is far more complex than currently realized.The inhibition of learned fear is an evolutionarily conserved behavioral adaptation that is essential for survival. This learning process, known as extinction, involves rapid reversal of previously learned contingencies, which depend on gene expression and protein synthesis. Impairments in the neural mechanisms that promote this beneficial response to threat can lead to the development of posttraumatic stress disorder ...

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Section: Discussionmentioning

confidence: 96%

mentioning

confidence: 99%

Neocortical Tet3-mediated accumulation of 5-hydroxymethylcytosine promotes rapid behavioral adaptation

Wei

Zhao

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

166

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“…Such studies have implicated hmC regulation in aspects of learning and memory, hippocampal neurogenesis, and neuronal activity-regulated gene expression (35,41,42). Coupled with reports that a redistribution of genomic hmC accompanies some forms of neural plasticity (35,36), these findings suggest that hmC regulation may be intimately involved in CNS function. However, additional research will be required to distinguish more precisely the direct roles for hmC remodeling in neuronal plasticity from the secondary effects related to altered Tet function during neural development.…”

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confidence: 80%

“…1). In addition, Tet1 and Tet3 mRNA levels have been found to respond to neuronal activity (35,36), raising the possibility that neuronal activity in newly formed circuits helps drive the increase in hmC in the brain and shapes the profile of hmC across the neuronal genome. It is notable that currently available evidence suggests that most hmC in the brain occurs in the CG context (>99% in mouse adult and fetal cortex) (8).…”

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confidence: 99%

Reading the unique DNA methylation landscape of the brain: Non-CpG methylation, hydroxymethylation, and MeCP2

Kinde

Gabel

Gilbert

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

208

191

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DNA methylation at CpG dinucleotides is an important epigenetic regulator common to virtually all mammalian cell types, but recent evidence indicates that during early postnatal development neuronal genomes also accumulate uniquely high levels of two alternative forms of methylation, non-CpG methylation and hydroxymethylation. Here we discuss the distinct landscape of DNA methylation in neurons, how it is established, and how it might affect the binding and function of protein readers of DNA methylation. We review studies of one critical reader of DNA methylation in the brain, the Rett syndrome protein methyl CpG-binding protein 2 (MeCP2), and discuss how differential binding affinity of MeCP2 for non-CpG and hydroxymethylation may affect the function of this methyl-binding protein in the nervous system.M ethylation of cytosines at the carbon 5 position (5-methylcytosine, mC) constitutes the most common covalent modification of vertebrate genomic DNA. Traditionally, cytosine methylation in vertebrate genomes has been viewed as largely restricted to CpG dinucleotide (CG) sequences, providing a stable epigenetic mark that mediates long-term transcriptional silencing. Indeed, 60-90% of all CGs are methylated in mammalian genomes, and CG methylation (mCG) has been shown to play critical roles in genomic imprinting, X-chromosome inactivation, cellular differentiation, and development (1). In addition, the disruption of cellular DNA methylation patterns has been linked to human disease, including multiple cancers (2, 3).Evidence that DNA methylation has a uniquely important role in the brain emerged almost two decades ago with the discovery of the prominent methyl-DNA-binding protein, methyl-CpG-binding protein 2 (MeCP2), and the later identification that mutations in MeCP2 give rise to the X-linked neurological disorder Rett syndrome (RTT) (4-6). Subsequent studies also have identified neurodevelopmental disorders associated with mutations in DNA methyltransferases (7), suggesting that both the enzymatic "writers" of DNA methylation patterns and the "readers" of these marks have important roles in the brain. In this context, new studies from several laboratories have uncovered extensive cytosine modification in the brain beyond mCG. Non-CG methylation (CH methylation or mCH, in which H = A, C, or T) is now appreciated to accumulate in the human and mouse brain postnatally, reaching levels similar to that of mCG in the neuronal genome (8, 9). Moreover, oxidation of mC by the ten-eleven translocation (Tet) family of dioxygenases leads to the selective accumulation of 5-hydroxymethylcytosine (hmC) in the adult brain, together with its more highly oxidized derivatives 5-formylcytosine and 5-carboxylcytosine (10, 11). This finding suggests that hmC may act as an intermediate in an active DNA demethylation pathway, though growing evidence also suggests that hmC may serve as a stable neuronal epigenetic mark in its own right (12).The discovery of these previously unidentified brain-enriched forms of DNA methylation provides...

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“…In addition, fetusspecific and adult-specific Differentially hydroxyl methylated regions (DhMRs) in exons and CpG islands have been identified [57]. In the brain, 5hmC makes the neurons highly plastic and highly adaptable so that they can receive signals and trigger long-lasting functional changes [58]. While further studies are required to determine additional regulatory functions of 5hmC independent from that of 5mC, these studies imply that 5hmC-mediated epigenetic regulation may broadly impact human brain development, and age-related dysregulation of DNA methylation could contribute to memory deficits and the molecular pathogenesis of neuro developmental disorders.…”

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confidence: 99%

Epigenetics: Integrating Genetic Programs, Brain Development and Emergent Phenotypes

Weaver¹

2014

Cell Dev Biol

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Adaptation to environmental changes is based on the perpetual generation of new phenotypes. Modern biology has focused on the role of epigenetic mechanisms in facilitating the adaptation of organisms to changing environments through alterations in gene expression. Inherited and/or acquired epigenetic factors are relatively stable and have regulatory roles in numerous genomic activities that translate into phenotypic outcomes. Evidence that dietary and pharmacological interventions have the potential to reverse environment-induced modification of epigenetic states (e.g., early life experience, nutrition, medication, infection etc.) has provided an additional stimulus for understanding the biological basis of individual differences in cognitive abilities and disorders of the brain. It has been suggested that the accurate quantification of the relative contribution of heritable genetic and epigenetic variation is essential for understanding phenotypic divergence and adaptation in changing environments, a process requiring stable modulation of gene expression. The main challenge for epigenetics in psychology and psychiatry is to determine how experiences and environmental cues influence the expression of neuronal genes to produce long-term individual differences in behavior, cognition, personality and mental health. To this end, focusing on DNA and histone modifications and their initiators, mediators and readers may provide new inroads for understanding the molecular basis phenotypic plasticity and disorders of the brain. In this review, we survey recent developments revealing epigenetic aspects of mental illness, as well as review some of the challenges of current approaches and some future directions in the field of behavioral epigenetics. Early Life Development and Transmission of PhenotypeHuman development not only involves the biological and physical aspects of growth, but also the cognitive and social aspects. Early in life, neuronal circuits are created and connections between neurons undergo remodeling as they develop their adult functional properties in response to intrinsic (genomic) and extrinsic (environmental) cues. The capacity of a single genotype to exhibit variable phenotypes in different environments is common across all species and is often highly adaptive and forms the basis for 'phenotypic plasticity'. Historically, the relationship between the genome and the environment has been presented under the framework of gene-environment interaction (or genotype-environment interaction, G×E). The challenge for developmental psychology and psychiatry has been to integrate findings from genetics into the study of personality and our understanding of the pathophysiology of mental illness. For example: (1) common genetic risk factors and rare mutations such as Single-Nucleotide Polymorphisms (SNPs) and variation in the number of nucleotide repeats such as Copy-Number Variants (CNVs) mapped in GenomeWide Association Studies (GWAS) account for only a small fraction (1-2%) of the total risk for comple...

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TET1 Controls CNS 5-Methylcytosine Hydroxylation, Active DNA Demethylation, Gene Transcription, and Memory Formation

Cited by 371 publications

References 38 publications

Neocortical Tet3-mediated accumulation of 5-hydroxymethylcytosine promotes rapid behavioral adaptation

Neocortical Tet3-mediated accumulation of 5-hydroxymethylcytosine promotes rapid behavioral adaptation

Reading the unique DNA methylation landscape of the brain: Non-CpG methylation, hydroxymethylation, and MeCP2

Epigenetics: Integrating Genetic Programs, Brain Development and Emergent Phenotypes

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