Crystal Structure of TET2-DNA Complex: Insight into TET-Mediated 5mC Oxidation

Hu, Lulu; Li, Ze; Cheng, Jingdong; Rao, Qinhui; Gong, W.; Liu, Mengjie; Shi, Yujiang Geno; Zhu, Jiayu; Wang, Ping; Xu, Yanhui

doi:10.1016/j.cell.2013.11.020

Cited by 365 publications

(515 citation statements)

References 74 publications

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“…We next determined whether TET2 repression is associated with growth inhibitory effect of TET2 in prostate cancer. We also demonstrated that TET2 growth inhibitory ability was associated with the C-terminal domain important for its enzymatic activity 27 ( Supplementary Fig. 9).…”

Section: Resultsmentioning

confidence: 67%

TET2 repression by androgen hormone regulates global hydroxymethylation status and prostate cancer progression

et al. 2015

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Modulation of epigenetic patterns has promising efficacy for treating cancer. 5-Hydroxymethylated cytosine (5-hmC) is an epigenetic mark potentially important in cancer. Here we report that 5-hmC is an epigenetic hallmark of prostate cancer (PCa) progression. A member of the ten-eleven translocation (TET) proteins, which catalyse the oxidation of methylated cytosine (5-mC) to 5-hmC, TET2, is repressed by androgens in PCa. Androgen receptor (AR)-mediated induction of the miR-29 family, which targets TET2, are markedly enhanced in hormone refractory PCa (HRPC) and its high expression predicts poor outcome of PCa patients. Furthermore, decreased expression of miR-29b results in reduced tumour growth and increased TET2 expression in an animal model of HRPC. Interestingly, global 5-hmC modification regulated by miR-29b represses FOXA1 activity. A reduction in 5-hmC activates PCa-related key pathways such as mTOR and AR. Thus, DNA modification directly links the TET2-dependent epigenetic pathway regulated by AR to 5-hmC-mediated tumour progression.

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Section: Resultsmentioning

confidence: 67%

TET2 repression by androgen hormone regulates global hydroxymethylation status and prostate cancer progression

et al. 2015

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“…Although Methylcytosine can be modified to hydroxymethylcytosine by the Tet family of dioxygenases, Tet1-3. Current evidence demonstrates that the oxidative conversion of methylcytosine to hydroxymethylcytosine by the Tet enzymes occurs at CG dinucleotides, as is consistent with the overwhelming proportion of hydroxymethylation occurring as hmCG rather than hmCH (8,37). Additionally, Tet enzymes are capable of catalyzing further oxidation of hmC to formylcytosine and carboxylcytosine to yield substrates for Tdg, ultimately resulting in the generation of a nonmethylated cytosine (10,11).…”

mentioning

confidence: 76%

“…Indeed, given that few individual genomic sites exhibit significant levels of CH hydroxymethylation (hmCH), it remains unclear whether hmCH exists as a genuine species in vivo. Recent characterization of the Tet enzymes has demonstrated a strong preference for oxidation of mCG compared with mCH, providing a possible explanation for the low levels of hmCH (37). However, these steady-state measurements do not rule out the possibility that hmCH is turned over rapidly after conversion from mCH.…”

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confidence: 83%

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.

216

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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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“…Additionally, TET enzymes may prefer CG sites (Hu et al 2013) which raises the intriguing possibility that mCH may be resistant to oxidation and elimination. Our understanding of the effects of mC/hmC on gene expression and genome organization with aging is in its infancy.…”

Section: Nature and Regulation Of Dna Modificationsmentioning

confidence: 99%

Analysis of DNA modifications in aging research

et al. 2018

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As geroscience research extends into the role of epigenetics in aging and age-related disease, researchers are being confronted with unfamiliar molecular techniques and data analysis methods that can be difficult to integrate into their work. In this review, we focus on the analysis of DNA modifications, namely cytosine methylation and hydroxymethylation, through nextgeneration sequencing methods. While older techniques for modification analysis performed relative quantitation across regions of the genome or examined average genome levels, these analyses lack the desired specificity, rigor, and genomic coverage to firmly establish the nature of genomic methylation patterns and their response to aging. With recent methodological advances, such as whole genome bisulfite sequencing (WGBS), bisulfite oligonucleotide capture sequencing (BOCS), and bisulfite amplicon sequencing (BSAS), cytosine modifications can now be readily analyzed with base-specific, absolute quantitation at both cytosine-guanine dinucleotide (CG) and non-CG sites throughout the genome or within specific regions of interest by next-generation sequencing. Additional advances, such as oxidative bisulfite conversion to differentiate methylation from hydroxymethylation and analysis of limited input/single-cells, have great promise for continuing to expand epigenomic capabilities. This review provides a background on DNA modifications, the current state-of-theart for sequencing methods, bioinformatics tools for converting these large data sets into biological insights, and perspectives on future directions for the field.

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Crystal Structure of TET2-DNA Complex: Insight into TET-Mediated 5mC Oxidation

Cited by 365 publications

References 74 publications

TET2 repression by androgen hormone regulates global hydroxymethylation status and prostate cancer progression

TET2 repression by androgen hormone regulates global hydroxymethylation status and prostate cancer progression

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

Analysis of DNA modifications in aging research

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