The presence of 5-hydroxymethylcytosine in animal deoxyribonucleic acid

Penn, N. W.; Suwalski, R.; O'Riley, C.; Bojanowski, Krzysztof; Yura, R.

doi:10.1042/bj1260781

Cited by 252 publications

(184 citation statements)

References 21 publications

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“…5mC can be hydroxylated by TETs to become 5-hydroxymethylcytosine (5hmC). 5hmC was first reported in bacteriophage nucleic acids [8] and later in animal cells [9]. The occurrence of 5hmC in animal cells was debated until 2009, when two groups independently confirmed the presence of 5hmC in the animal genome [7,10].…”

mentioning

confidence: 88%

Active DNA demethylation by oxidation and repair

Gong

Zhu

2011

Cell Res

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confidence: 88%

Active DNA demethylation by oxidation and repair

Gong

Zhu

2011

Cell Res

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“…Despite a report more than 40 years ago suggesting the existence of hmC in mammalian genomes (28), the presence of significant levels of hmC in CNS neurons remained unexplored until recently. The persistent failure to observe genomic hydroxymethylation likely reflected the inability of traditional bisulfite sequencing methods to distinguish between methylated and hydroxymethylated sites.…”

mentioning

confidence: 99%

“…This paper results from the Arthur M. Sackler Colloquium of the National Academy of Sciences, "Epigenetic Changes in the Developing Brain: Effects on Behavior," held March [28][29]2014, at the National Academy of Sciences in Washington, DC. The complete program and video recordings of most presentations are available on the NAS website at www.nasonline.org/Epigenetic_changes.…”

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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.

212

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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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“…Similar to the removal of a methyl group in sterol metabolism, the hydroxymethyl moiety is liable to be expelled as formic acid (Shyadehi et al, 1996). Hydroxymethylcytosine was first detected some 35 years ago and even then was suspected to be higher in the brain than in other tissues such as the liver (Penn et al, 1972). Levels were noted to increase in the brain with development into adulthood (Penn, 1976).…”

Section: Demethylases: Removing the Markmentioning

confidence: 99%

CpG Methylation in Neurons: Message, Memory, or Mask?

Sharma

Gavin

Grayson

2010

Neuropsychopharmacol

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The study of CpG methylation of genomic DNA in neurons has emerged from the shadow of cancer biology into a fundamental investigation of neuronal physiology. This advance began with the discovery that catalytic and receptor proteins related to the insertion and recognition of this chemical mark are robustly expressed in neurons. At the smallest scale of analysis is the methylation of a single cytosine base within a regulatory cognate sequence. This singular alteration in a nucleotide can profoundly modify transcription factor binding with a consequent effect on the primary 'transcript'. At the single promoter level, the methylation-demethylation of CpG islands and associated alterations in local chromatin assemblies creates a type of cellular 'memory' capable of long-term regulation of transcription particularly in stages of brain development, differentiation, and maturation. Finally, at the genome-wide scale, methylation studies from post-mortem brains suggest that CpG methylation may serve to cap the genome into active and inactive territories introducing a 'masking' function. This may facilitate rapid DNA-protein interactions by ambient transcriptional proteins onto actively networked gene promoters. Beyond this broad portrayal, there are vast gaps in our understanding of the pathway between neuronal activity and CpG methylation. These include the regulation in post-mitotic neurons of the executor proteins, such as the DNA methyltransferases, the elusive and putative demethylases, and the interactions with histone modifying enzymes.

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The presence of 5-hydroxymethylcytosine in animal deoxyribonucleic acid

Cited by 252 publications

References 21 publications

Active DNA demethylation by oxidation and repair

Active DNA demethylation by oxidation and repair

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

CpG Methylation in Neurons: Message, Memory, or Mask?

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