scholarly journals Direct decarboxylation of Ten-eleven translocation-produced 5-carboxylcytosine in mammalian genomes forms a new mechanism for active DNA demethylation

2021 ◽  
Author(s):  
Yang Feng ◽  
Juan-Juan Chen ◽  
Neng-Bin Xie ◽  
Jiang-Hui Ding ◽  
Xue-Jiao You ◽  
...  
Keyword(s):  
Cytosine Methylation ◽  
Dna Demethylation ◽  
Epigenetic Mark ◽  
Active Dna Demethylation ◽  
Mammalian Genomes ◽  
Higher Eukaryotes ◽  
Dna Cytosine Methylation

DNA cytosine methylation (5-methylcytosine, 5mC) is the most important epigenetic mark in higher eukaryotes. 5mC in genomes is dynamically controlled by the writers and erasers. DNA (cytosine-5)-methyltransferases (DNMTs) are responsible...

scholarly journals DNA Demethylation Pathways: Recent Insights

2013 ◽  
Vol 5 ◽  
pp. GEG.S12143 ◽  
Author(s):  
Cong-jun Li
Keyword(s):  
Dna Methylation ◽  
Mammalian Cells ◽  
De Novo ◽  
Dna Demethylation ◽  
Epigenetic Mark ◽  
Sequencing Technologies ◽  
Active Dna Demethylation ◽  
Mammalian Genomes ◽  
Genome Context

DNA methylation is a major epigenetic regulatory mechanism for gene expression and cell differentiation. Until recently, it was still unclear how unmethylated regions in mammalian genomes are protected from de novo methylation and whether or not active demethylating activity is involved. Even the role of molecules and the mechanisms underlying the processes of active demethylation itself is blurred. Emerging sequencing technologies have led to recent insights into the dynamic distribution of DNA methylation during development and the role of this epigenetic mark within a distinct genome context, such as the promoters, exons, or imprinted control regions. This review summarizes recent insights on the dynamic nature of DNA methylation and demethylation, as well as the mechanisms regulating active DNA demethylation in mammalian cells, which have been fundamental research interests in the field of epigenomics.

scholarly journals DNA demethylation is initiated in the central cells of Arabidopsis and rice

2016 ◽  
Vol 113 (52) ◽  
pp. 15138-15143 ◽  
Author(s):  
Kyunghyuk Park ◽  
M. Yvonne Kim ◽  
Martin Vickers ◽  
Jin-Sup Park ◽  
Youbong Hyun ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Dna Methyltransferase ◽  
Cytosine Methylation ◽  
Dna Demethylation ◽  
Central Cell ◽  
Dna Modification ◽  
Active Dna Demethylation ◽  
Genome Wide ◽  
Regulatory Functions ◽  
Global Reduction

Cytosine methylation is a DNA modification with important regulatory functions in eukaryotes. In flowering plants, sexual reproduction is accompanied by extensive DNA demethylation, which is required for proper gene expression in the endosperm, a nutritive extraembryonic seed tissue. Endosperm arises from a fusion of a sperm cell carried in the pollen and a female central cell. Endosperm DNA demethylation is observed specifically on the chromosomes inherited from the central cell in Arabidopsis thaliana, rice, and maize, and requires the DEMETER DNA demethylase in Arabidopsis. DEMETER is expressed in the central cell before fertilization, suggesting that endosperm demethylation patterns are inherited from the central cell. Down-regulation of the MET1 DNA methyltransferase has also been proposed to contribute to central cell demethylation. However, with the exception of three maize genes, central cell DNA methylation has not been directly measured, leaving the origin and mechanism of endosperm demethylation uncertain. Here, we report genome-wide analysis of DNA methylation in the central cells of Arabidopsis and rice—species that diverged 150 million years ago—as well as in rice egg cells. We find that DNA demethylation in both species is initiated in central cells, which requires DEMETER in Arabidopsis. However, we do not observe a global reduction of CG methylation that would be indicative of lowered MET1 activity; on the contrary, CG methylation efficiency is elevated in female gametes compared with nonsexual tissues. Our results demonstrate that locus-specific, active DNA demethylation in the central cell is the origin of maternal chromosome hypomethylation in the endosperm.

scholarly journals The exploration of N6-deoxyadenosine methylation in mammalian genomes

2021 ◽  
Author(s):  
Xuwen Li ◽  
Zijian Zhang ◽  
Xinlong Luo ◽  
Jacob Schrier ◽  
Andrew D. Yang ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Regulatory Mechanism ◽  
Epigenetic Mark ◽  
Dna Modification ◽  
Biological Processes ◽  
Environmental Stress Response ◽  
Mammalian Genomes ◽  
Higher Eukaryotes ◽  
And Function ◽  
Major Progress

AbstractN6-methyladenine (N6-mA, m6dA, or 6mA), a prevalent DNA modification in prokaryotes, has recently been identified in higher eukaryotes, including mammals. Although 6mA has been well-studied in prokaryotes, the function and regulatory mechanism of 6mA in eukaryotes are still poorly understood. Recent studies indicate that 6mA can serve as an epigenetic mark and play critical roles in various biological processes, from transposable-element suppression to environmental stress response. Here, we review the significant advances in methodology for 6mA detection and major progress in understanding the regulation and function of this non-canonical DNA methylation in eukaryotes, predominantly mammals.

scholarly journals Critical roles of DNA demethylation in the activation of ripening-induced genes and inhibition of ripening-repressed genes in tomato fruit

2017 ◽  
Vol 114 (22) ◽  
pp. E4511-E4519 ◽  
Author(s):  
Zhaobo Lang ◽  
Yihai Wang ◽  
Kai Tang ◽  
Dengguo Tang ◽  
Tatsiana Datsenka ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Fruit Ripening ◽  
Tomato Fruit ◽  
Dna Demethylation ◽  
Epigenetic Mark ◽  
Loss Of Function ◽  
Active Dna Demethylation ◽  
Tomato Fruit Ripening ◽  
Induced Genes ◽  
Environmental Responses

DNA methylation is a conserved epigenetic mark important for genome integrity, development, and environmental responses in plants and mammals. Active DNA demethylation in plants is initiated by a family of 5-mC DNA glycosylases/lyases (i.e., DNA demethylases). Recent reports suggested a role of active DNA demethylation in fruit ripening in tomato. In this study, we generated loss-of-function mutant alleles of a tomato gene, SlDML2, which is a close homolog of the Arabidopsis DNA demethylase gene ROS1. In the fruits of the tomato mutants, increased DNA methylation was found in thousands of genes. These genes included not only hundreds of ripening-induced genes but also many ripening-repressed genes. Our results show that SlDML2 is critical for tomato fruit ripening and suggest that active DNA demethylation is required for both the activation of ripening-induced genes and the inhibition of ripening-repressed genes.

scholarly journals Tet proteins: on track towards DNA demethylation?

2012 ◽  
Vol 3 (5) ◽  
pp. 395-402 ◽  
Author(s):  
Nathalie Véron
Keyword(s):  
Dna Methylation ◽  
Enzymatic Activity ◽  
Dna Demethylation ◽  
Epigenetic Mark ◽  
Developmental Processes ◽  
Tet Proteins ◽  
Active Dna Demethylation ◽  
Demethylation Pathway ◽  
Cellular Integrity ◽  
Tet Protein

AbstractDynamic DNA methylation is a prerequisite for many developmental processes and maintenance of cellular integrity. In mammals however, mechanisms of active DNA demethylation have for long been elusive. The discovery of the ten-eleven translocation (Tet) family of enzymes that oxidize 5-methylcytosine (5mC) to 5-hydroxymethylcytosine (5hmC), 5-formylcytosine (5fC) or 5-carboxylcytosine (5caC) provided new means by which DNA methylation could actively be reversed. This review focuses on the possible mechanisms of DNA demethylation via Tet proteins and their metabolites 5hmC, 5fC and 5caC. Additionally, it discusses the roles of the three Tet protein family members Tet1, Tet2 and Tet3 as developmental regulators, probably in part independent of their enzymatic activity. By contrast, recent evidence suggests a function of 5hmC as an epigenetic mark on its own, going beyond the expectation of only acting as an intermediate in an active DNA demethylation pathway.

scholarly journals DNA Methylation in Cancer and Development: An Evolving Paradigm

Blood ◽  
2017 ◽  
Vol 130 (Suppl_1) ◽  
pp. SCI-50-SCI-50
Author(s):  
Maria E. Figueroa
Keyword(s):  
Dna Methylation ◽  
Gene Regulation ◽  
Cytosine Methylation ◽  
Conflicts Of Interest ◽  
Cpg Islands ◽  
Dna Methyltransferases ◽  
Dna Demethylation ◽  
Epigenetic Mark ◽  
Cpg Dinucleotides ◽  
Promoter Dna

DNA methylation is an epigenetic mark which, in mammals, occurs primarily on position 5 of cytosines, especially at those found in the context of CpG dinucleotides. This CpG methylation is known to play a major role in gene regulation. Cytosine methylation is regulated by the DNA methyltransferases, responsible for adding the methyl group to unmethylated CpGs, and the TET dioxygenases, involved in the DNA demethylation pathway. Initially, DNA methylation was believed to be important mainly for gene silencing through promoter DNA methylation, especially at CpG-rich promoters containing CpG islands. However, our understanding of the role that DNA methylation plays in gene regulation during normal development and how this process becomes deregulated in cancer, has evolved in recent years. Moreover, the discovery of frequent mutations in DNMT3A and TET2 both in clonal hematopoiesis of indeterminate significance as well as in many hematological malignancies has brought new interest into understanding what role DNA methylation plays in normal HSC function as well as how it contributes to malignant transformation. In this session, we will review the current understanding in the field of DNA methylation and gene regulation, and present data on DNA methylation in normal HSCs as well as the role that this epigenetic mark plays during leukemic transformation in acute myeloid leukemia. Disclosures No relevant conflicts of interest to declare.

scholarly journals Somatic DNA demethylation generates tissue-specific methylation states and impacts flowering time

2021 ◽  
Author(s):  
Ben P Williams ◽  
Linsdey A Bechen ◽  
Deborah A Pohlmann ◽  
Mary Gehring
Keyword(s):  
Cytosine Methylation ◽  
Epigenetic Modification ◽  
Dna Demethylation ◽  
Dna Glycosylases ◽  
Wild Type ◽  
Gene Body Methylation ◽  
Tissue Specific ◽  
Coding Regions ◽  
Active Dna Demethylation ◽  
Somatic Tissues

Cytosine methylation is a reversible epigenetic modification to DNA. In plants, removal of cytosine methylation is accomplished by the four members of the DME family of 5-methylcytosine DNA glycosylases. Demethylation by DME is critical for seed development. Consequently, determining the function of the entire gene family in somatic tissues by mutant analysis has not been possible. Here, we bypassed the reproductive defects of dme mutants to create somatic quadruple homozygous mutants of the entire DME family. dme; ros1; dml2; dml3 (drdd) leaves exhibit hypermethylated genomes compared to both wild-type plants and rdd triple mutants, indicating functional redundancy among all four demethylases. Targets of demethylation include regions co-targeted by RNA-directed DNA methylation and, surprisingly, CG gene body methylation, indicating dynamic methylation at these little-understood sites. Additionally, many tissue-specific methylation differences are absent in drdd, suggesting a role for active demethylation in generating divergent epigenetic states across wild-type tissues. Furthermore, drdd plants display a striking early flowering phenotype, which is associated with 5′ hypermethylation and transcriptional down-regulation of FLOWERING LOCUS C. Active DNA demethylation is therefore required for proper methylation patterning across somatic tissues and defines the epigenetic landscape of both intergenic and coding regions.

scholarly journals Global increase in DNA methylation during orange fruit development and ripening

2019 ◽  
Vol 116 (4) ◽  
pp. 1430-1436 ◽  
Author(s):  
Huan Huang ◽  
Ruie Liu ◽  
Qingfeng Niu ◽  
Kai Tang ◽  
Bo Zhang ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Fruit Ripening ◽  
Tomato Fruit ◽  
Dna Demethylation ◽  
Epigenetic Mark ◽  
Dna Hypermethylation ◽  
Active Dna Demethylation ◽  
Orange Fruit ◽  
Global Increase ◽  
Genomic Regions

DNA methylation is an important epigenetic mark involved in many biological processes. The genome of the climacteric tomato fruit undergoes a global loss of DNA methylation due to active DNA demethylation during the ripening process. It is unclear whether the ripening of other fruits is also associated with global DNA demethylation. We characterized the single-base resolution DNA methylomes of sweet orange fruits. Compared with immature orange fruits, ripe orange fruits gained DNA methylation at over 30,000 genomic regions and lost DNA methylation at about 1,000 genomic regions, suggesting a global increase in DNA methylation during orange fruit ripening. This increase in DNA methylation was correlated with decreased expression of DNA demethylase genes. The application of a DNA methylation inhibitor interfered with ripening, indicating that the DNA hypermethylation is critical for the proper ripening of orange fruits. We found that ripening-associated DNA hypermethylation was associated with the repression of several hundred genes, such as photosynthesis genes, and with the activation of hundreds of genes, including genes involved in abscisic acid responses. Our results suggest important roles of DNA methylation in orange fruit ripening.

scholarly journals Delineation of the First Human Mendelian Disorder of the DNA Demethylation Machinery: TET3 Deficiency

2019 ◽  
Author(s):  
David B. Beck ◽  
Ana Petracovici ◽  
Chongsheng He ◽  
Hannah W. Moore ◽  
Raymond J. Louie ◽  
...  
Keyword(s):  
Intellectual Disability ◽  
Developmental Disorders ◽  
Cytosine Methylation ◽  
Catalytic Domain ◽  
Dna Demethylation ◽  
Global Developmental Delay ◽  
Facial Dysmorphism ◽  
Epigenetic Mark ◽  
Mendelian Disorder ◽  
Growth Abnormalities

ABSTRACTGermline pathogenic variants in chromatin-modifying enzymes are a common cause of pediatric developmental disorders. These enzymes catalyze reactions that regulate epigenetic inheritance via histone post-translational modifications and DNA methylation. Cytosine methylation of DNA (5mC) is the quintessential epigenetic mark, yet no human Mendelian disorder of DNA demethylation has been delineated. Here, we describe in detail the first Mendelian disorder caused by disruption of DNA demethylation. TET3 is a methylcytosine dioxygenase that initiates DNA demethylation during early zygote formation, embryogenesis, and neuronal differentiation and is intolerant to haploinsufficiency in mice and humans. Here we identify and characterize 11 cases of human TET3 deficiency in 8 families with the common phenotypic features of intellectual disability/global developmental delay, hypotonia, autistic traits, movement disorders, growth abnormalities, and facial dysmorphism. Mono-allelic frameshift and nonsense variants in TET3 occur throughout the coding region. Mono-allelic and bi-allelic missense variants localize to conserved residues with all but one occurring within the catalytic domain and most displaying hypomorphic function in a catalytic activity assay. TET3 deficiency shows substantial phenotypic overlap with other Mendelian disorders of the epigenetic machinery, including intellectual disability and growth abnormalities, underscoring shared disease mechanisms.

scholarly journals Targeted DNA demethylation of the Arabidopsis genome using the human TET1 catalytic domain

2018 ◽  
Vol 115 (9) ◽  
pp. E2125-E2134 ◽  
Author(s):  
Javier Gallego-Bartolomé ◽  
Jason Gardiner ◽  
Wanlu Liu ◽  
Ashot Papikian ◽  
Basudev Ghoshal ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Cytosine Methylation ◽  
Catalytic Domain ◽  
Epigenetic Modification ◽  
High Specificity ◽  
Dna Demethylation ◽  
Late Flowering ◽  
Dna Cytosine Methylation ◽  
Activate Gene ◽  
Target Effects

DNA methylation is an important epigenetic modification involved in gene regulation and transposable element silencing. Changes in DNA methylation can be heritable and, thus, can lead to the formation of stable epialleles. A well-characterized example of a stable epiallele in plants is fwa, which consists of the loss of DNA cytosine methylation (5mC) in the promoter of the FLOWERING WAGENINGEN (FWA) gene, causing up-regulation of FWA and a heritable late-flowering phenotype. Here we demonstrate that a fusion between the catalytic domain of the human demethylase TEN-ELEVEN TRANSLOCATION1 (TET1cd) and an artificial zinc finger (ZF) designed to target the FWA promoter can cause highly efficient targeted demethylation, FWA up-regulation, and a heritable late-flowering phenotype. Additional ZF–TET1cd fusions designed to target methylated regions of the CACTA1 transposon also caused targeted demethylation and changes in expression. Finally, we have developed a CRISPR/dCas9-based targeted demethylation system using the TET1cd and a modified SunTag system. Similar to the ZF–TET1cd fusions, the SunTag–TET1cd system is able to target demethylation and activate gene expression when directed to the FWA or CACTA1 loci. Our study provides tools for targeted removal of 5mC at specific loci in the genome with high specificity and minimal off-target effects. These tools provide the opportunity to develop new epialleles for traits of interest, and to reactivate expression of previously silenced genes, transgenes, or transposons.

Sign in / Sign up

Export Citation Format

Share Document