Getting rid of DNA methylation

doi:10.1016/j.tcb.2013.09.001

Trends in Cell Biology

Volume 24, Issue 2, February 2014, Pages 136-143

https://doi.org/10.1016/j.tcb.2013.09.001 Get rights and content

Highlights

•
DNA methylation is a widespread epigenetic trait that is remodeled during development.
•
Multiple routes for DNA demethylation exist across the animal and plant kingdoms.
•
5mC removal from the genome requires DNA synthesis-dependent and -independent processes.
•
Tet proteins convert 5mC to 5hmC, an intermediate in active and passive demethylation.

Methylation of cytosine within DNA is associated with transcriptional repression and genome surveillance. In plants and animals, conserved pathways exist to establish and maintain this epigenetic mark. Mechanisms underlining its removal are, however, diverse and controversial and can depend on DNA synthesis (passive) or be independent of it (active). Ten–eleven translocation (Tet)-mediated conversion of 5-methylcytosine (5mC) into 5-hydroxymethylcytosine (5hmC) has recently been evoked as a possible mechanism in the initiation of active and passive DNA demethylation. This review discuses the recent progress in this exciting area.

Section snippets

DNA methylation

The epigenetic control of genome function, such as replication, repair and transcription, involves covalent modifications to genomic DNA and to the associated nucleosomes. Genomic DNA can be modified in several ways, including methylation of different nucleotide bases [1] (see Glossary). In this review we focus on methylation of the fifth carbon of the cytosine ring (5mC), predominantly in the context of CpG dinucleotides [2]. The capacity to methylate DNA is probably an ancient feature in

The origins of DNA methylation

In bacteria, DNA methylation was initially reported in restriction–modification (R–M) systems [5]. These specialized domains facilitate the safe exchange of genetic material between related bacterial strains, discriminating against exchange between foreign or invading DNA molecules [6]. In addition, DNA methylation has been implicated in controlling the timing of DNA replication [7] and repair [8]. These functions are predominantly controlled by so-called ‘orphan’ methyltransferases, which have

Reversing DNA methylation

Because DNA methylation influences gene expression, there is a need to modulate 5mC levels in the genome during the animal and plant life cycle. In the course of evolution, members of the plant and animal kingdoms have engineered strategies to allow changes to, and loss of, DNA methylation. DNA demethylation is widespread and has been well characterized among important developmental processes including gametogenesis, fertilization, and somatic cell reprogramming (Figure 2).

The role of Tet enzymes

Methylation is not the only way that eukaryotic cells can modify their DNA. Evolution has provided examples of other mechanisms for modifying DNA. For instance, African trypanosomes, protozoan parasites that have been suggested to have very low levels of 5mC in their genome [47], can chemically modify their DNA generating β-D-glucopyranosylmethyluracil (base-J) residues [48]. Although the biological function of this DNA modification remains to be fully understood, the reactions required for the

Concluding remarks

Conserved mechanisms for DNA methylation in plants, animals, and fungi suggest an ancient origin for this important epigenetic mediator. By contrast, multitudes of processes may induce DNA demethylation and, at first sight, there appears to be little conservation between the mechanisms reported for the plant and animal kingdoms. Despite the vast literature, there is no clear consensus regarding a single or preferred mechanism for DNA demethylation in mammals 40, 79. This is probably because

Glossary

Active DNA demethylation: occurs via the direct removal or conversion of methyl groups from DNA independent of DNA replication.
Base excision repair (BER): a complex pathway of enzymes that correct lesions in DNA to ensure that mutations are excised, repaired, and sealed.
DNA methylation: the addition of a methyl group (CH₃) to the cytosine or adenine DNA nucleotide.
Imprinted genes: show parent-of-origin expression and are controlled by epigenetic processes such as DNA methylation.
Passive DNA

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Cited by (62)

SUMO1 Modification Stabilizes TET3 Protein and Increases Colorectal Cancer Radiation Therapy Sensitivity
2023, International Journal of Radiation Oncology Biology Physics
The aim of this work was to explore the role and mechanism of active DNA demethylase in colorectal cancer (CRC) radiation sensitization and better understand the function of DNA demethylation in tumor radiosensitization.
Tested the effect of ten-eleven translocation 3 (TET3) overexpression on the sensitivity of CRC to radiation therapy through G2/M arrest, apoptosis, and clonogenic suppression. TET3 knockdown HCT 116 and TET3 knockdown LS 180 cell lines were constructed by siRNA technology, and the effect of exogenous knockdown of TET3 on radiation-induced apoptosis, cell cycle arrest, DNA damage, and clone formation in CRC cells were detected. The co-localization of TET3 and small ubiquitin-like modifier 1 (SUMO1), SUMO2/3 was detected by immunofluorescence and cytoplasmic–nuclear extraction, and the interaction between TET3 and SUMO1, SUMO2/3 was detected by a coimmunoprecipitation assay.
The malignant phenotype and radiosensitivity of CRC cell lines were favorably linked with TET3 protein and mRNA expression. TET3 is upregulated in 23 of the 27 tumor types investigated, including colon cancer. TET3 was shown to correlate with the CRC pathologic malignancy grade positively. Overexpression of TET3 in CRC cell lines increased radiation-induced apoptosis, G2/M phase arrest, DNA damage, and clonal suppression in vitro. The binding region of TET3 and SUMO2/3 was located at 833-1795 AA except for K1012, K1188, K1397, and K1623. SUMOylation of TET3 increased the stability of the TET3 protein without changing its nuclear localization.
We report the sensitizing role of TET3 protein in the radiation of CRC cells, depending on SUMO1 modification of TET3 at the lysine sites (K479, K758, K1012, K1188, K1397, K1623), in turn stabilizing TET3 expression in the nucleus and subsequently increasing the sensitivity of CRC to radiation therapy. Together, this study highlights the potentially critical role of TET3 SUMOylation in radiation regulation, which may contribute to an enhanced understanding of the relationship between DNA demethylation and radiation therapy.
Loss of Thymine DNA Glycosylase Causes Dysregulation of Bile Acid Homeostasis and Hepatocellular Carcinoma
2020, Cell Reports
Citation Excerpt :
However, the biological mechanisms underlying the link between gender, T2D, and HCC are unclear. Aberrant DNA methylation at CpG sites is a common molecular lesion in cancer, often resulting in genomic instability and silencing of specific tumor suppressor genes (Britschgi et al., 2008; Fleuriel et al., 2009; Jones and Baylin, 2002, 2007; Piccolo and Fisher, 2014). Widespread changes in the methylation landscape in cancer cells lead to the aberrant regulation of genes that promote cellular growth and proliferation, culminating in the disruption of cell-cycle control, angiogenesis, and invasion (Hendrich et al., 1999; Jones et al., 1992; Lian et al., 2012).
Thymine DNA glycosylase (TDG) is a nuclear receptor coactivator that plays an essential role in the maintenance of epigenetic stability in cells. Here, we demonstrate that the conditional deletion of TDG in adult mice results in a male-predominant onset of hepatocellular carcinoma (HCC). TDG loss leads to a prediabetic state, as well as bile acid (BA) accumulation in the liver and serum of male mice. Consistent with these data, TDG deletion led to dysregulation of the farnesoid X receptor (FXR) and small heterodimer partner (SHP) regulatory cascade in the liver. FXR and SHP are tumor suppressors of HCC and play an essential role in BA and glucose homeostasis. These results indicate that TDG functions as a tumor suppressor of HCC by regulating a transcriptional program that protects against the development of glucose intolerance and BA accumulation in the liver.
Epigenetic changes and photosynthetic plasticity in response to environment
2019, Environmental and Experimental Botany
Citation Excerpt :
The distribution of DNA methylation along the genome shows enrichment at noncoding regions such as centromeric heterochromatin and interspersed repetitive elements (To et al., 2015; Zilberman et al., 2007). The methylation of DNA is performed by specialized enzymes known as DNA methyltransferases (DNAmet), which add a methyl group (CH3) from the S-adenosylmethionine (SAM) donor into the 5´position of the pyrimidine ring of 2′-deoxycytosine to form 5-methyl-2′-deoxycytosine (5mdC), without interfering with the base pairing (Finnegan et al., 1998; Piccolo and Fisher, 2014). In plants, DNAmet are able to catalyze “maintenance” methylation or “de novo” methylation in CG, CHG or CHH motifs (in which H is A, T, or C).
Without photosynthesis, life on earth as we know it would be impossible. Advances in our understanding of how light harvesting and carbon fixation work have traditionally been driven by biochemical and molecular approaches with the goal of increasing crop yield. However, environmental challenges are putting the survival of many plants at risk due to photosynthetic inbalance. Epigenetic regulation has only recently been recognized as an important player in the response to changes in key environmental conditions such as light, temperature and drought, and while there has been scattered research on the topic, it has not yet been collated into a review. Here we focus on epigenetics’ affect on photosynthesis-related carbon fixation pathways and identify important directions for future research. For instance, during the perception of light, epigenetic regulation mediates a complex and flexible series of events, including histone acetylation and DNA demethylation, to promote expression of several genes involved in carbon fixation, such as RuBisCO and PEPC in C₃ and C₄ plants, respectively. On the other hand, the crucial role of deacetylases of histones HD1 and HDA15 and the possible participation of miRNAs during light/dark signaling and light harvesting, respectively, reveal an unexplored connection between light signaling and epigenetic regulation during photosynthesis. In the present review, we highlight how euchromatin configuration helps in the acquisition of drought tolerance and efficient stomata conductance. Therefore, we suggest that several drought-sensitive crops could be improved with the use of miRNA to optimize photosynthetic stomata conductance and gas exchange.
Epigenetics and Regeneration: An Overview
2019, Epigenetics and Regeneration
Tissue regeneration represents a paradigm of stem cell function in the adult. Although stem cells have been identified in most mammalian tissues and organs, the ability of these tissues to differentiate is remarkably different and is thought to depend both on extrinsic and intrinsic mechanisms. Among the latter, epigenetic mechanisms regulate the dramatic reprogramming of stem cell function that occurs upon injury, which leads to the reactivation of otherwise silent developmental programs.
Here I will provide an overview of the epigenetic mechanisms involved in tissue homeostasis and regeneration and of how epigenetic reprogramming contributes to tissue remodeling. To this end, I will use an integrative approach that includes developmental and evolutionary perspectives. In addition, I will discuss how targeting the epigenome through either epi-drugs or lifestyle interventions can be used to stimulate the regenerative potential of mammalian tissues and organs. Given the loss of homeostasis and regenerative potential that occurs with age, epigenetic manipulations represent a new approach in the field of regenerative medicine for a variety of age-associated degenerative disorders.
The Intrinsic Role of Epigenetics in Axonal Regeneration
2019, Epigenetics and Regeneration
Axonal injury causes devastating neural impairment, which is often permanent after central nervous system (CNS) damage. Axon regeneration failure is largely responsible for these long-term deficits and poor functional recovery, and is attributable to cell-intrinsic mechanisms and to the nonpermissive cell-extrinsic environment, which together limit axon regrowth.
One of the main intrinsic barriers to functional regeneration of mature mammalian neurons is the epigenome. Whereas in the peripheral nervous system (PNS), injury unlocks mature neurons’ intrinsic axonal growth transcriptional program, this does not occur in the CNS.
Here we review the intrinsic and extrinsic mechanisms of axonal regeneration, with a focus on the fundamental role of the epigenome in this process. We highlight the common and different mechanisms that take place upon injury to the CNS and PNS, identifying key factors that may contribute to the impaired regeneration potential of the CNS.
DNA methylation protects against cisplatin-induced kidney injury by regulating specific genes, including interferon regulatory factor 8
2017, Kidney International
DNA methylation is an epigenetic mechanism that regulates gene transcription without changing primary nucleotide sequences. In mammals, DNA methylation involves the covalent addition of a methyl group to the 5-carbon position of cytosine by DNA methyltransferases (DNMTs). The change of DNA methylation and its pathological role in acute kidney injury (AKI) remain largely unknown. Here, we analyzed genome-wide DNA methylation during cisplatin-induced AKI by reduced representation bisulfite sequencing. This technique identified 215 differentially methylated regions between the kidneys of control and cisplatin-treated animals. While most of the differentially methylated regions were in the intergenic, intronic, and coding DNA sequences, some were located in the promoter or promoter-regulatory regions of 15 protein-coding genes. To determine the pathological role of DNA methylation, we initially examined the effects of the DNA methylation inhibitor 5-aza-2'-deoxycytidine and showed it increased cisplatin-induced apoptosis in a rat kidney proximal tubular cell line. We further established a kidney proximal tubule-specific DNMT1 (PT-DNMT1) knockout mouse model, which showed more severe AKI during cisplatin treatment than wild-type mice. Finally, interferon regulatory factor 8 (Irf8), a pro-apoptotic factor, was identified as a hypomethylated gene in cisplatin-induced AKI, and this hypomethylation was associated with a marked induction of Irf8. In the rat kidney proximal tubular cells, the knockdown of Irf8 suppressed cisplatin-induced apoptosis, supporting a pro-death role of Irf8 in renal tubular cells. Thus, DNA methylation plays a protective role in cisplatin-induced AKI by regulating specific genes, such as Irf8.

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Trends in Cell Biology

ReviewGetting rid of DNA methylation

Highlights

Section snippets

DNA methylation

The origins of DNA methylation

Reversing DNA methylation

The role of Tet enzymes

Concluding remarks

Glossary

Trends Biochem. Sci.

J. Mol. Biol.

J. Biol. Chem.

Curr. Biol.

J. Mol. Biol.

Curr. Opin. Plant Biol.

Cell

Mol. Cell

Mech. Dev.

Dev. Biol.

Mol. Cell

Cell

Cell

Curr. Biol.

Cell

Cell

Cell

Cell

Mol. Cell

Protein Expr. Purif.

Mol. Cell

Cell Stem Cell

Dev. Cell

Cell

Cell

J. Biol. Chem.

Cell

Cell

Cell

Cell Stem Cell

DNA methylation in thermophilic bacteria: N4-methylcytosine, 5-methylcytosine, and N6-methyladenine

Nucleic Acids Res.

Eukaryotic cytosine methyltransferases

Annu. Rev. Biochem.

Genome-wide evolutionary analysis of eukaryotic DNA methylation

Science

Epigenetic gene regulation in the bacterial world

Microbiol. Mol. Biol. Rev.

Importance of state of methylation of oriC GATC sites in initiation of DNA replication in Escherichia coli

EMBO J.

DNA methylation and the formation of heterochromatin in Neurospora crassa

Heredity (Edinb.)

DNA methylation patterns and epigenetic memory

Genes Dev.

Structural basis for recognition of hemi-methylated DNA by the SRA domain of human UHRF1

Nature

The SRA domain of UHRF1 flips 5-methylcytosine out of the DNA helix

Nature

Establishing, maintaining and modifying DNA methylation patterns in plants and animals

Nat. Rev. Genet.

Epigenetic reprogramming in plant and animal development

Science

Review
Getting rid of DNA methylation