Dynamic Readers for 5-(Hydroxy)Methylcytosine and Its Oxidized Derivatives

Spruijt, Cornelia G.; Gnerlich, Felix; Smits, Arne H.; Pfaffeneder, Toni; Jansen, Pascal W.T.C.; Bauer, Christina; Münzel, Martin; Wagner, Mirko; Müller, Markus; Khan, Feroz; Eberl, H. Christian; Mensinga, Anneloes; Brinkman, Arie B.; Lephikov, Konstantin; Müller, Udo; Walter, Jörn; Boelens, Rolf; Ingen, Hugo van; Leonhardt, Heinrich; Carell, Thomas; Vermeulen, Michiel

doi:10.1016/j.cell.2013.02.004

Cited by 915 publications

(1,026 citation statements)

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“…However, an understanding of how 5-hmC influences this process within the context of learning and memory has not been achieved. It has recently been suggested that 5-hmC can regulate gene expression by recruiting "readers" to regions across the genome in which this epigenetic mark accumulates (40). On the basis of our genome-wide 5-hmC mapping data, we reasoned that the presence of 5-hmC within intronic and intergenic regions influences the local chromatin landscape, thereby providing a link between this epigenetic modification and experiencedependent regulation of gene expression.…”

Section: Genome-wide Patterns Of 5-hmc Are Dramatically Redistributed Inmentioning

confidence: 94%

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

Wei

Zhao

et al. 2014

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

169

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: Genome-wide Patterns Of 5-hmc Are Dramatically Redistributed Inmentioning

confidence: 94%

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

Wei

Zhao

et al. 2014

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

169

166

View full text Add to dashboard Cite

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“…A second reason is that the functions of TET proteins likely extend beyond DNA demethylation to a more direct involvement in the epigenetic regulation of gene transcription. Specifically, all three oxi-mC species-5hmC, 5fC, and 5caC-are likely to function as epigenetic modifications that affect chromatin conformation and gene expression by recruiting "reader" proteins that recognize these modifications (29,49,50). 5hmC is a particularly stable and abundant mark, comprising ∼5-10, 40, and ∼1% of total 5mC in ES cells, Purkinje neurons, and immune cells, respectively (47,51).…”

Section: Discussionmentioning

confidence: 99%

Dissecting the dynamic changes of 5-hydroxymethylcytosine in T-cell development and differentiation

Tsagaratou

Äijö

Lio

et al. 2014

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

144

165

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The discovery of Ten Eleven Translocation proteins, enzymes that oxidize 5-methylcytosine (5mC) in DNA, has revealed novel mechanisms for the regulation of DNA methylation. We have mapped 5-hydroxymethylcytosine (5hmC) at different stages of T-cell development in the thymus and T-cell differentiation in the periphery. We show that 5hmC is enriched in the gene body of highly expressed genes at all developmental stages and that its presence correlates positively with gene expression. Further emphasizing the connection with gene expression, we find that 5hmC is enriched in active thymus-specific enhancers and that genes encoding key transcriptional regulators display high intragenic 5hmC levels in precursor cells at those developmental stages where they exert a positive effect. Our data constitute a valuable resource that will facilitate detailed analysis of the role of 5hmC in T-cell development and differentiation.thymic development | epigenetics

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“…These include the SAD/SRA, which recognizes 5mC in DNA; EVE, which binds DNA with 5hmC; and the PUA, which binds modified RNA (including the YTH family which binds m 6 A containing RNA) 20, 68, 111, 112, 113, 114, 115. Another family displaying this fold, the ASCH domain, was predicted to bind several modified bases, and is found fused to or operonically associated with the N 6 A‐MTase domain on multiple occasions in bacteria 15, 112 (Fig.…”

Section: Multiple Domains Potentially Discriminate M6a Marks In Dnamentioning

confidence: 99%

Adenine methylation in eukaryotes: Apprehending the complex evolutionary history and functional potential of an epigenetic modification

2015

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While N6‐methyladenosine (m6A) is a well‐known epigenetic modification in bacterial DNA, it remained largely unstudied in eukaryotes. Recent studies have brought to fore its potential epigenetic role across diverse eukaryotes with biological consequences, which are distinct and possibly even opposite to the well‐studied 5‐methylcytosine mark. Adenine methyltransferases appear to have been independently acquired by eukaryotes on at least 13 occasions from prokaryotic restriction‐modification and counter‐restriction systems. On at least four to five instances, these methyltransferases were recruited as RNA methylases. Thus, m6A marks in eukaryotic DNA and RNA might be more widespread and diversified than previously believed. Several m6A‐binding protein domains from prokaryotes were also acquired by eukaryotes, facilitating prediction of potential readers for these marks. Further, multiple lineages of the AlkB family of dioxygenases have been recruited as m6A demethylases. Although members of the TET/JBP family of dioxygenases have also been suggested to be m6A demethylases, this proposal needs more careful evaluation.Also watch the Video Abstract.

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Dynamic Readers for 5-(Hydroxy)Methylcytosine and Its Oxidized Derivatives

Cited by 915 publications

References 61 publications

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

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

Dissecting the dynamic changes of 5-hydroxymethylcytosine in T-cell development and differentiation

Adenine methylation in eukaryotes: Apprehending the complex evolutionary history and functional potential of an epigenetic modification

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