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Pediatric T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive malignancy resulting from overproduction of immature T-cells in the thymus and is typified by widespread alterations in DNA methylation. As survival rates for relapsed T-ALL remain dismal (10 to 25%), development of targeted therapies to prevent relapse is key to improving prognosis. Whereas mutations in the DNA demethylating enzyme TET2 are frequent in adult T-cell malignancies, TET2 mutations in T-ALL are rare. Here, we analyzed RNA-sequencing data of 321 primary T-ALLs, 20 T-ALL cell lines, and 25 normal human tissues, revealing that TET2 is transcriptionally repressed or silenced in 71% and 17% of T-ALL, respectively. Furthermore, we show that TET2 silencing is often associated with hypermethylation of the TET2 promoter in primary T-ALL. Importantly, treatment with the DNA demethylating agent, 5-azacytidine (5-aza), was significantly more toxic to TET2 -silenced T-ALL cells and resulted in stable re-expression of the TET2 gene. Additionally, 5-aza led to up-regulation of methylated genes and human endogenous retroviruses (HERVs), which was further enhanced by the addition of physiological levels of vitamin C, a potent enhancer of TET activity. Together, our results clearly identify 5-aza as a potential targeted therapy for TET2 -silenced T-ALL., Competing Interests: The authors declare no competing interest., (Copyright © 2021 the Author(s). Published by PNAS.)

Indeed, tumors are a significant health concern worldwide, and understanding the underlying mechanisms of tumor development is crucial for effective prevention and treatment. Epigenetics, which refers to changes in gene expression that are not caused by alterations in the DNA sequence itself, plays a critical role in the entire process of tumor development. It goes without saying that the effect of methylation on tumors is a significant aspect of epigenetics. Among the methylation modifications, DNA methylation is an important part, which plays a regulatory role in tumor-related genes. Ten-eleven translocation 2 (TET2) is a highly influential protein involved in the modification of DNA methylation. Its primary role is associated with the suppression of tumor development, making it a significant player in cancer research. However, TET2 is frequently mentioned in hematological diseases, its role in solid tumors has received little attention. Studying the changes of TET2 in solid tumors and the regulatory mechanism will facilitate its investigation as a clinical target for targeted therapy and may also provide directions for clinical treatment of malignant tumors., (© 2024. The Author(s), under exclusive licence to Federación de Sociedades Españolas de Oncología (FESEO).)

N 6 -methyladenine (6mdA) is a widespread DNA modification in bacteria. More recently, 6mdA has also been characterized in mammalian DNA. However, measurements of 6mdA abundance and profiles are often very dissimilar between studies, even when performed on DNA from identical mammalian cell types. Using comprehensive bioinformatics analyses of published data and novel experimental approaches, we reveal that efforts to assay 6mdA in mammals have been severely compromised by bacterial contamination, RNA contamination, technological limitations, and antibody nonspecificity. These complications render 6mdA an exceptionally problematic DNA modification to study and have resulted in erroneous detection of 6mdA in several mammalian systems. Together, our results strongly imply that the evidence published to date is not sufficient to support the presence of 6mdA in mammals., (Copyright © 2020 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works. Distributed under a Creative Commons Attribution NonCommercial License 4.0 (CC BY-NC).)

Main Conclusion: The present review summarizes recent advances in the understanding of 6mA in DNA as an emergent epigenetic mark with distinctive characteristics, discusses its importance in plant genomes, and highlights its chemical nature and functions. Adenine methylation is an epigenetic modification present in DNA (6mA) and RNA (m6A) that has a regulatory function in many cellular processes. This modification occurs through a reversible reaction that covalently binds a methyl group, usually at the N 6 position of the purine ring. This modification carries biophysical properties that affect the stability of nucleic acids as well as their binding affinity with other molecules. DNA 6mA has been related to genome stability, gene expression, DNA replication, and repair mechanisms. Recent advances have shown that 6mA in plant genomes is related to development and stress response. In this review, we present recent advances in the understanding of 6mA in DNA as an emergent epigenetic mark with distinctive characteristics. We discuss the key elements of this modification, focusing mainly on its importance in plant genomes. Furthermore, we highlight its chemical nature and the regulatory effects that it exerts on gene expression and plant development. Finally, we emphasize the functions of 6mA in photosynthesis, stress, and flowering., (© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

The genomes of bacteria, archaea, and phage contain small amounts of C 5 -methylcytosine, N 4 -methylcytosine, and N 6 -methyladenine. Base methylation takes place after DNA replication and is catalyzed by DNA methyltransferases that recognize specific target sequences. Prokaryotic DNA methyltransferases can be classified into two main types: (1) belonging to restriction-modification systems and (2) solitary (or "orphan") enzymes that lack a restriction enzyme partner. All known roles of DNA methylation involve control of interactions between DNA-binding proteins and their cognate sites. Such roles include protection from DNA restriction, strand discrimination during mismatch repair, cell cycle control, and regulation of transcription. DNA methylation often affects the interaction of bacterial pathogens with their hosts, raising the possibility of epigenetic therapies for infectious diseases., (© 2022. The Author(s), under exclusive license to Springer Nature Switzerland AG.)

Chromatin, consisting of deoxyribonucleic acid (DNA) wrapped around histone proteins, facilitates DNA compaction and allows identical DNA code to confer many different cellular phenotypes. This biological versatility is accomplished in large part by post-translational modifications to histones and chemical modifications to DNA. These modifications direct the cellular machinery to expand or compact specific chromatin regions and mark certain regions of the DNA as important for cellular functions. While each of the four bases that make up DNA can be modified (Iyer et al., Prog Mol Biol Transl Sci. 101:25-104, 2011), this chapter will focus on methylation of the 6th position on adenines (6mA). 6mA is a prevalent modification in unicellular organisms and until recently was thought to be restricted to them. A flurry of conflicting studies have proposed that 6mA either does not exist, is present at low levels, or is present at relatively high levels and regulates complex processes in different multicellular eukaryotes. Here, we will briefly describe the history of 6mA, examine its evolutionary conservation, and evaluate the current methods for detecting 6mA. We will discuss the proteins that have been reported to bind and regulate 6mA and examine the known and potential functions of this modification in eukaryotes. Finally, we will close with a discussion of the ongoing debate about whether 6mA exists as a directed DNA modification in multicellular eukaryotes., (© 2022. The Author(s), under exclusive license to Springer Nature Switzerland AG.)

6-methyladenine (6mA) is fairly abundant in nuclear DNA of basal fungi, ciliates and green algae. In these organisms, 6mA is maintained near transcription start sites in ApT context by a parental-strand instruction dependent maintenance methyltransferase and is positively associated with transcription. In animals and plants, 6mA levels are high only in organellar DNA. The 6mA levels in nuclear DNA are very low. They are attributable to nucleotide salvage and the activity of otherwise mitochondrial METTL4, and may be considered as a price that cells pay for adenine methylation in RNA and/or organellar DNA. Cells minimize this price by sanitizing dNTP pools to limit 6mA incorporation, and by converting 6mA that has been incorporated into DNA back to adenine. Hence, 6mA in nuclear DNA should be described as an epigenetic mark only in basal fungi, ciliates and green algae, but not in animals and plants., (© 2020 The Authors. BioEssays published by Wiley Periodicals LLC.)

The universality of DNA methylation as an epigenetic regulatory mechanism belongs to all biological kingdoms. However, while eukaryotic systems have been the primary focus of DNA methylation studies, the molecular mechanisms in prokaryotes are less known. Nevertheless, DNA methylation in prokaryotes plays a pivotal role in many cellular processes such as defense systems against exogenous DNA, cell cycle dynamics, and gene expression, including virulence. Thanks to single-molecule DNA sequencing technologies, genome-wide identification of methylated DNA is becoming feasible on a large scale, providing the possibility to investigate more deeply the presence, variability, and roles of DNA methylation. Here, we present an overview of the multifaceted roles of DNA methylation in prokaryotes and suggest research directions and tools which can enable us to better understand the contribution of DNA methylation to prokaryotic genome evolution and adaptation. In particular, we emphasize the need to understand the presence and role of transgenerational inheritance, as well as the impact of epigenomic signatures on adaptation and genome evolution. Research directions and the importance of novel computational tools are underlined. [ABSTRACT FROM AUTHOR]

T-cell acute lymphoblastic leukemia (T-ALL) is a type of hematologic tumor with malignant proliferation of hematopoietic progenitor cells. However, traditional clinical treatment of T-ALL included chemotherapy and stem cell transplantation always lead to recurrence and poor prognosis, thus new therapeutic targets and drugs are urgently needed for T-ALL treatment. In this study, we showed that TET1 (ten-eleven translocation 1), a key participant of DNA epigenetic control, which catalyzes the conversion of 5-methylcytosine (5mC) to 5-hydroxymethylcytosine (5hmC) to modulate gene expression, was highly upregulated in human T-ALL and negatively correlated with the prognosis of patients. Knockdown of TET1 suppressed T-ALL growth and progression, suggesting that TET1 inhibition maybe an effective way to fight T-ALL via DNA epigenetic modulation. Combining structure-guided virtual screening and cell-based high-throughput screening of FDA-approved drug library, we discovered that auranofin, a gold-containing compound, is a potent TET1 inhibitor. Auranofin inhibited the catalytic activity of TET1 through competitive binding to its substrates binding pocket and thus downregulated the genomic level of 5hmC marks and particularly epigenetically reprogramed the expression of oncogene c-Myc in T-ALL in TET1-dependent manner and resulted in suppression of T-ALL in vitro and in vivo. These results revealed that TET1 is a potential therapeutic target in human T-ALL and elucidated the mechanism that TET1 inhibitor auranofin suppressed T-ALL through the TET1/5hmC/c-Myc signaling pathway. Our work thus not only provided mechanism insights for T-ALL treatment, but also discovered potential small molecule therapeutics for T-ALL. [ABSTRACT FROM AUTHOR]

Mobility of transposable elements (TEs) frequently leads to insertional mutations in functional DNA regions. In the potentially immortal germline, TEs are effectively suppressed by the Piwi-piRNA pathway. However, in the genomes of ageing somatic cells lacking the effects of the pathway, TEs become increasingly mobile during the adult lifespan, and their activity is associated with genomic instability. Whether the progressively increasing mobilization of TEs is a cause or a consequence of ageing remains a fundamental problem in biology. Here we show that in the nematode Caenorhabditis elegans, the downregulation of active TE families extends lifespan. Ectopic activation of Piwi proteins in the soma also promotes longevity. Furthermore, DNA N6-adenine methylation at TE stretches gradually rises with age, and this epigenetic modification elevates their transcription as the animal ages. These results indicate that TEs represent a novel genetic determinant of ageing, and that N6-adenine methylation plays a pivotal role in ageing control. Transposable elements in somatic cells become increasingly mobile during ageing. Here, the authors show that in the nematode Caenorhabditis elegans, downregulation of transposable elements extends lifespan, and that their increases with age are coupled with progressively growing N6-adenine methylation in these genetic loci. [ABSTRACT FROM AUTHOR]

N6‐methyldeoxyadenosine (6mA) is a chemical alteration of DNA, observed across all realms of life. Although the functions of 6mA are well understood in bacteria and protists, its roles in animal genomes have been controversial. We show that 6mA randomly accumulates in early embryos of the cnidarian Hydractinia symbiolongicarpus, with a peak at the 16‐cell stage followed by clearance to background levels two cell cycles later, at the 64‐cell stage—the embryonic stage at which zygotic genome activation occurs in this animal. Knocking down Alkbh1, a putative initiator of animal 6mA clearance, resulted in higher levels of 6mA at the 64‐cell stage and a delay in the initiation of zygotic transcription. Our data are consistent with 6mA originating from recycled nucleotides of degraded m6A‐marked maternal RNA postfertilization. Therefore, while 6mA does not function as an epigenetic mark in Hydractinia, its random incorporation into the early embryonic genome inhibits transcription. In turn, Alkbh1 functions as a genomic 6mA "cleaner," facilitating timely zygotic genome activation. Given the random nature of genomic 6mA accumulation and its ability to interfere with gene expression, defects in 6mA clearance may represent a hitherto unknown cause of various pathologies. Synopsis: The presence and functions of N6‐methylation of deoxyadenosine (6mA) in animal genomes are disputed. This study shows that N6‐methyladenosine (m6A)‐decorated maternal RNA is the source of 6mA in cnidarian embryonic genomes, from which it has to be removed for initiation of zygotic transcription.Rapid degradation of m6A‐marked maternal RNAs generates a nucleotide pool containing m6A.After NTP‐to‐dNTP conversion by a ribonucleotide reductase, 6mA is randomly incorporated into the embryonic genome.Genomic 6mA interferes with embryonic transcription.Removal of 6mA by the 6mA dioxygenase Alkbh1 facilitates timely zygotic genome activation. [ABSTRACT FROM AUTHOR]

DNA methylation constitutes one of the pillars of epigenetics, relying on covalent bonds for addition and/or removal of chemically distinct marks within the major groove of the double helix. DNA methyltransferases, enzymes which introduce methyl marks, initially evolved in prokaryotes as components of restriction‐modification systems protecting host genomes from bacteriophages and other invading foreign DNA. In early eukaryotic evolution, DNA methyltransferases were horizontally transferred from bacteria into eukaryotes several times and independently co‐opted into epigenetic regulatory systems, primarily via establishing connections with the chromatin environment. While C5‐methylcytosine is the cornerstone of plant and animal epigenetics and has been investigated in much detail, the epigenetic role of other methylated bases is less clear. The recent addition of N4‐methylcytosine of bacterial origin as a metazoan DNA modification highlights the prerequisites for foreign gene co‐option into the host regulatory networks, and challenges the existing paradigms concerning the origin and evolution of eukaryotic regulatory systems. [ABSTRACT FROM AUTHOR]

N6-methyldeoxyadenine (6mA) has recently been reported as a prevalent DNA modification in eukaryotes. The Tetrahymena thermophila MTA1 complex consisting of four subunits, namely MTA1, MTA9, p1, and p2, is the first identified eukaryotic 6mA methyltransferase (MTase) complex. Unlike the prokaryotic 6mA MTases which have been biochemically and structurally characterized, the operation mode of the MTA1 complex remains largely elusive. Here, we report the cryogenic electron microscopy structures of the quaternary MTA1 complex in S-adenosyl methionine (SAM)-bound (2.6 Å) and S-adenosyl homocysteine (SAH)-bound (2.8 Å) states. Using an AI-empowered integrative approach based on AlphaFold prediction and chemical cross-linking mass spectrometry, we further modeled a near-complete structure of the quaternary complex. Coupled with biochemical characterization, we revealed that MTA1 serves as the catalytic core, MTA1, MTA9, and p1 likely accommodate the substrate DNA, and p2 may facilitate the stabilization of MTA1. These results together offer insights into the molecular mechanism underpinning methylation by the MTA1 complex and the potential diversification of MTases for N6-adenine methylation. [ABSTRACT FROM AUTHOR]

Simple Summary: Recent advances in exome sequencing and comprehensive genomic studies have shed new light on the pathogenesis and mutational landscape of Angioimmunoblastic T-cell lymphoma (AITL). The essential pathogenic role of recurrent TET2, DNMT3A, IDH2, and RHOA mutations in AITL has been identified. Notably, the detection of TET2 mutations in bystander B cells in AITL samples has allowed new mechanistic advances in AITL combined with B-cell lymphoma. In this review, we highlight the current role of TET2 mutations in the pathogenesis of AITL and how mutational crosstalk in TET2 and other partner genes (RHOA, DNMT3A, and IDH2) cooperate to contribute to the disease. In addition, we elaborate on recent advances in AITL frequently comprising B-cell lymphoma and discuss the potential prospects of targeting TET2 as an anti-AITL agent. Angioimmunoblastic T-cell lymphoma (AITL), a type of malignant lymphoma with unique genomic aberrations, significant clinicopathological features, and poor prognosis, is characterized by immune system dysregulation. Recent sequencing studies have identified recurrent mutations and interactions in tet methylcytosine dioxygenase 2 (TET2), ras homology family member A (RHOA), DNA methyltransferase 3 alpha (DNMT3A), and mitochondrial isocitrate dehydrogenase II (IDH2). Notably, since B-cell lymphomas are frequently observed along with AITL, this review first summarizes its controversial mechanisms based on traditional and recent views. Epigenetic regulation represented by TET2 plays an increasingly important role in understanding the multi-step and multi-lineage tumorigenesis of AITL, providing new research directions and treatment strategies for patients with AITL. Here, we review the latest advances in our understanding of AITL and highlight relevant issues that have yet to be addressed in clinical practice. [ABSTRACT FROM AUTHOR]

The placenta has a methylome dramatically unlike that of any somatic cell type. Among other distinctions, it features low global DNA methylation, extensive “partially methylated domains” packed in dense heterochromatin and methylation of hundreds of CpG islands important in somatic development. These features attract interest in part because a substantial fraction of human cancers feature the exact same phenomena, suggesting parallels between epigenome formation in placentation and cancer. Placenta also features an expanded set of imprinted genes, some of which come about by distinctive developmental pathways. Recent discoveries, some from far outside the placental field, shed new light on how the unusual placental epigenetic state may arise. Nonetheless, key questions remain unresolved. [ABSTRACT FROM AUTHOR]

DNA methylation is treated as an important epigenetic mark in various biological activities. In the past, a large number of articles focused on 5 mC while lacking attention to N6-methyladenine (6 mA). The presence of 6 mA modification was previously discovered only in prokaryotes. Recently, with the development of detection technologies, 6 mA has been found in several eukaryotes, including protozoans, metazoans, plants, and fungi. The importance of 6 mA in prokaryotes and single-celled eukaryotes has been widely accepted. However, due to the incredibly low density of 6 mA and restrictions on detection technologies, the prevalence of 6 mA and its role in biological processes in eukaryotic organisms are highly debated. In this review, we first summarize the advantages and disadvantages of 6 mA detection methods. Then, we conclude existing reports on the prevalence of 6 mA in eukaryotic organisms. Next, we highlight possible methyltransferases, demethylases, and the recognition proteins of 6 mA. In addition, we summarize the functions of 6 mA in eukaryotes. Last but not least, we summarize our point of view and put forward the problems that need further research. [ABSTRACT FROM AUTHOR]

DNA methylation is one of the most important epigenetic modifications and is closely related with several biological processes such as regulation of gene transcription and the development of non-malignant diseases. The prevailing dogma states that DNA methylation in eukaryotes occurs essentially through 5-methylcytosine (5mC) but recently adenine methylation was also found to be present in eukaryotes. In mouse embryonic stem cells, 6-methyladenine (6mA) was associated with the repression and silencing of genes, particularly in the X-chromosome, known to play an important role in cell fate determination. Here, we have demonstrated that 6mA is a ubiquitous eukaryotic epigenetic modification that is put in place during epigenetically sensitive periods such as embryogenesis and fetal development. In somatic cells there are clear tissue specificity in 6mA levels, with the highest 6mA levels being observed in the brain. In zebrafish, during the first 120 h of embryo development, from a single pluripotent cell to an almost fully formed individual, 6mA levels steadily increase. An identical pattern was observed over embryonic days 7–21 in the mouse. Furthermore, exposure to a neurotoxic environmental pollutant during the same early life period may led to a decrease in the levels of this modification in female rats. The identification of the periods during which 6mA epigenetic marks are put in place increases our understanding of this mammalian epigenetic modification, and raises the possibility that it may be associated with developmental processes. [ABSTRACT FROM AUTHOR]

Orofacial clefts (OFCs) have multiple etiologies and likely result from an interplay between genetic and environmental factors. Within the last decade, studies have implicated specific epigenetic modifications and noncoding RNAs as additional facets of OFC etiology. Altered gene expression through DNA methylation and histone modification offer novel insights into how specific genes contribute to distinct OFC subtypes. Epigenetics research has also provided further evidence that cleft lip only (CLO) is a cleft subtype with distinct etiology. Polymorphisms or misexpression of genes encoding microRNAs, as well as their targets, contribute to OFC risk. The ability to experimentally manipulate epigenetic changes and noncoding RNAs in animal models, such as zebrafish, Xenopus, mice, and rats, has offered novel insights into the mechanisms of various OFC subtypes. Although much remains to be understood, recent advancements in our understanding of OFC etiology may advise future strategies of research and preventive care. [ABSTRACT FROM AUTHOR]

Over 17 and 160 types of chemical modifications have been identified in DNA and RNA, respectively. The interest in understanding the various biological functions of DNA and RNA modifications has lead to the cutting-edged fields of epigenomics and epitranscriptomics. Developing chemical and biological tools to detect specific modifications in the genome or transcriptome has greatly facilitated their study. Here, we review the recent technological advances in this rapidly evolving field. We focus on high-throughput detection methods and biological findings for these modifications, and discuss questions to be addressed as well. We also summarize third-generation sequencing methods, which enable long-read and single-molecule sequencing of DNA and RNA modification. [ABSTRACT FROM AUTHOR]