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https://www.readbyqxmd.com/read/29223032/dna-replication-and-associated-repair-pathways-are-involved-in-the-mutagenesis-of-methylated-cytosine
#1
Marketa Tomkova, Michael McClellan, Skirmantas Kriaucionis, Benjamin Schuster-Böckler
Transitions of cytosine to thymine in CpG dinucleotides are the most frequent type of mutations observed in cancer. This increased mutability is commonly explained by the presence of 5-methylcytosine (5mC) and its spontaneous hydrolytic deamination into thymine. Here, we describe observations that question whether spontaneous deamination alone causes the elevated mutagenicity of 5mC. Tumours with somatic mutations in DNA mismatch-repair genes or in the proofreading domain of DNA polymerase ε (Pol ε) exhibit more 5mC to T transitions than would be expected, given the kinetics of hydrolytic deamination...
November 24, 2017: DNA Repair
https://www.readbyqxmd.com/read/29203910/tet-proteins-safeguard-bivalent-promoters-from-de-novo-methylation-in-human-embryonic-stem-cells
#2
Nipun Verma, Heng Pan, Louis C Doré, Abhijit Shukla, Qing V Li, Bobbie Pelham-Webb, Virginia Teijeiro, Federico González, Andrei Krivtsov, Chan-Jung Chang, Eirini P Papapetrou, Chuan He, Olivier Elemento, Danwei Huangfu
TET enzymes oxidize 5-methylcytosine (5mC) to 5-hydroxymethylcytosine (5hmC), which can lead to DNA demethylation. However, direct connections between TET-mediated DNA demethylation and transcriptional output are difficult to establish owing to challenges in distinguishing global versus locus-specific effects. Here we show that TET1, TET2 and TET3 triple-knockout (TKO) human embryonic stem cells (hESCs) exhibit prominent bivalent promoter hypermethylation without an overall corresponding decrease in gene expression in the undifferentiated state...
December 4, 2017: Nature Genetics
https://www.readbyqxmd.com/read/29203887/age-dependent-increase-of-oxidative-stress-regulates-microrna-29-family-preserving-cardiac-health
#3
Johanna Heid, Chiara Cencioni, Roberto Ripa, Mario Baumgart, Sandra Atlante, Giuseppina Milano, Alessandro Scopece, Carsten Kuenne, Stefan Guenther, Valerio Azzimato, Antonella Farsetti, Giacomo Rossi, Thomas Braun, Giulio Pompilio, Fabio Martelli, Andreas M Zeiher, Alessandro Cellerino, Carlo Gaetano, Francesco Spallotta
The short-lived turquoise killifish Nothobranchius furzeri (Nfu) is a valid model for aging studies. Here, we investigated its age-associated cardiac function. We observed oxidative stress accumulation and an engagement of microRNAs (miRNAs) in the aging heart. MiRNA-sequencing of 5 week (young), 12-21 week (adult) and 28-40 week (old) Nfu hearts revealed 23 up-regulated and 18 down-regulated miRNAs with age. MiR-29 family turned out as one of the most up-regulated miRNAs during aging. MiR-29 family increase induces a decrease of known targets like collagens and DNA methyl transferases (DNMTs) paralleled by 5´methyl-cytosine (5mC) level decrease...
December 4, 2017: Scientific Reports
https://www.readbyqxmd.com/read/29186571/oxygen-gradients-can-determine-epigenetic-asymmetry-and-cellular-differentiation-via-differential-regulation-of-tet-activity-in-embryonic-stem-cells
#4
Simon Burr, Anna Caldwell, Mei Chong, Matteo Beretta, Stephen Metcalf, Matthew Hancock, Matthew Arno, Sucharitha Balu, Valeria Leon Kropf, Rajesh K Mistry, Ajay M Shah, Giovanni E Mann, Alison C Brewer
Graded levels of molecular oxygen (O2) exist within developing mammalian embryos and can differentially regulate cellular specification pathways. During differentiation, cells acquire distinct epigenetic landscapes, which determine their function, however the mechanisms which regulate this are poorly understood. The demethylation of 5-methylcytosine (5mC) is achieved via successive oxidation reactions catalysed by the Ten-Eleven-Translocation (Tet) enzymes, yielding the 5-hydroxymethylcytosine (5hmC) intermediate...
November 24, 2017: Nucleic Acids Research
https://www.readbyqxmd.com/read/29184981/the-tet-enzymes
#5
REVIEW
Peppi Koivunen, Tuomas Laukka
During the past decade, we have learnt that the most common DNA modification, 5-methylcytosine (5mC), playing crucial roles in development and disease, is not stable but can be actively reversed to its unmodified form via enzymatic catalysis involving the TET enzymes. These ground-breaking discoveries have been achieved thanks to technological advances in the detection of the oxidized forms of 5mC and to the boldness of individual scientists. The TET enzymes require molecular oxygen for their catalysis, making them important targets for hypoxia research...
November 28, 2017: Cellular and Molecular Life Sciences: CMLS
https://www.readbyqxmd.com/read/29175454/selective-inhibition-of-ctcf-binding-by-ias-directs-tet-mediated-reprogramming-of-5-hydroxymethylation-patterns-in-ias-transformed-cells
#6
Matthew Rea, Tyler Gripshover, Yvonne Fondufe-Mittendorf
Methylation at cytosine (5mC) is a fundamental epigenetic DNA modification recently associated with iAs-mediated carcinogenesis. In contrast, the role of 5-hydroxymethylcytosine (5hmC), the oxidation product of 5mC in iAs-mediated carcinogenesis is unknown. Here we assess the hydroxymethylome in iAs-transformed cells, showing that dynamic modulation of hydroxymethylated DNA is associated with specific transcriptional networks. Moreover, this pathologic iAs-mediated carcinogenesis is characterized by a shift toward a higher hydroxymethylation pattern genome-wide...
November 21, 2017: Toxicology and Applied Pharmacology
https://www.readbyqxmd.com/read/29158345/stable-oxidative-cytosine-modifications-accumulate-in-cardiac-mesenchymal-cells-from-type2-diabetes-patients-rescue-by-alpha-ketoglutarate-and-tet-tdg-functional-reactivation
#7
Francesco Spallotta, Chiara Cencioni, Sandra Atlante, Davide Garella, Mattia Cocco, Mattia Mori, Raffaella Mastrocola, Carsten Künne, Stefan Günther, Simona Nanni, Valerio Azzimato, Sven Zukunft, Angela Kornberger, Duran Sueruen, Frank Schnutgen, Harald von Melchner, Antonella Di Stilo, Manuela Aragno, Maarten Braspenning, Wim Van Criekinge, Miles J De Blasio, Rebecca H Ritchie, Germana Zaccagnini, Fabio Martelli, Antonella Farsetti, Ingrid Fleming, Thomas Braun, Andres Beiras-Fernandez, Bruno Botta, Massimo Collino, Massimo Bertinaria, Andreas M Zeiher, Carlo Gaetano
Rationale: Human cardiac mesenchymal cells (CMSCs) are a therapeutically-relevant primary cell population. Diabetes compromises CMSC function as consequence of metabolic alterations and incorporation of stable epigenetic changes. Objective: To investigate the role of α-ketoglutarate (αKG) in the epi-metabolic control of DNA demethylation in CMSCs. Methods and Results: Quantitative global analysis, methylated and hydroxymethylated DNA sequencing and gene specific GC methylation detection revealed an accumulation of 5mC, 5hmC and 5fC in the genomic DNA of human CMSCs isolated from diabetic (D) donors (D-CMSCs)...
November 20, 2017: Circulation Research
https://www.readbyqxmd.com/read/29118409/engineering-dna-backbone-interactions-results-in-tale-scaffolds-with-enhanced-5-methylcytosine-selectivity
#8
Preeti Rathi, Anna Witte, Daniel Summerer
Transcription activator-like effectors (TALEs) are DNA major-groove binding proteins widely used for genome targeting. TALEs contain an N-terminal region (NTR) and a central repeat domain (CRD). Repeats of the CRD selectively recognize each one DNA nucleobase, offering programmability. Moreover, repeats with selectivity for 5-methylcytosine (5mC) and its oxidized derivatives can be designed for analytical applications. However, both TALE domains also nonspecifically interact with DNA phosphates via basic amino acids...
November 8, 2017: Scientific Reports
https://www.readbyqxmd.com/read/29111854/the-effect-of-morphine-upon-dna-methylation-in-ten-regions-of-the-rat-brain
#9
Timothy M Barrow, Hyang-Min Byun, Xinyan Li, Chris Smart, Yong-Xiang Wang, Yacong Zhang, Andrea A Baccarelli, Liqiong Guo
Morphine is one of the most effective analgesics in medicine. However, its use is associated with the development of tolerance and dependence. Recent studies demonstrating epigenetic changes in the brain after exposure to opiates have provided insight into mechanisms possibly underlying addiction. In this study, we sought to identify epigenetic changes in ten regions of the rat brain following acute and chronic morphine exposure. We analyzed DNA methylation of six nuclear-encoded genes implicated in brain function (Bdnf, Comt, Il1b, Il6, Nr3c1, and Tnf) and three mitochondrially-encoded genes (Mtco1, Mtco2, and Mtco3), and measured global 5-methylcytosine (5mC) and 5-hydroxymethylcytosine (5hmC) levels...
November 7, 2017: Epigenetics: Official Journal of the DNA Methylation Society
https://www.readbyqxmd.com/read/29092933/integrating-dna-methylation-and-hydroxymethylation-data-with-the-mint-pipeline
#10
Raymond G Cavalcante, Snehal Patil, Yongseok Park, Laura S Rozek, Maureen A Sartor
DNA methylation (5mC) plays important roles in mammalian development, oncogenesis, treatment response, and responses to the environment. DNA hydroxymethylation (5hmC) is also an informative epigenetic mark with distinct roles in regulation and cancer. Gold-standard, widely used technologies (bisulfite conversion, followed by deep sequencing) cannot distinguish between 5mC and 5hmC. Therefore, additional experiments are required to differentiate the two marks, and in silico methods are needed to analyze, integrate, and interpret these data...
November 1, 2017: Cancer Research
https://www.readbyqxmd.com/read/29072898/the-epstein-barr-virus-b-zip-protein-zta-recognizes-specific-dna-sequences-containing-5-methylcytosine-and-5-hydroxymethylcytosine
#11
Desiree Tillo, Sreejana Ray, Khund-Sayeed Syed, Mary Rose Gaylor, Ximiao He, Jun Wang, Nima Assad, Stewart R Durell, Aleksey Porollo, Matthew T Weirauch, Charles Vinson
The Epstein-Barr virus (EBV) B-ZIP transcription factor Zta binds to many DNA sequences containing methylated CG dinucleotides. Using protein binding microarrays (PBMs), we analyzed the sequence specific DNA binding of Zta to four kinds of double-stranded DNA (dsDNA): (1) DNA containing cytosine in both strands, (2) DNA with 5-methylcytosine (5mC) in one strand and cytosine in the second strand, (3) DNA with 5-hydroxymethylcytosine (5hmC) in one strand and cytosine in the second strand, and (4) DNA in which both cytosines in all CG dinucleotides contain 5mC...
November 10, 2017: Biochemistry
https://www.readbyqxmd.com/read/29052184/bisulfite-sequencing-using-small-dna-amounts
#12
Susanne Edelmann, Stefan Scholten
Bisulfite sequencing (BS-seq) enables the detection of DNA methylation at cytosine residues (5mC) at single-nucleotide resolution. For many applications, a limiting factor of conventional BS-seq protocols is the high amount of DNA required, since the treatment with bisulfite causes severe DNA fragmentation. Here, we describe a post-bisulfite tagging method that accounts for this problem. Illumina-compatible BS-seq libraries can be obtained from as little as five single haploid maize cells, enabling whole genome BS-seq (WGBS) for the generation of genome-wide, cell-type specific DNA methylation profiles...
2018: Methods in Molecular Biology
https://www.readbyqxmd.com/read/29028987/in-silico-structural-modelling-of-multiple-epigenetic-marks-on-dna
#13
Konrad Krawczyk, Samuel Demharter, Bernhard Knapp, Charlotte M Deane, Peter Minary
Summary: There are four known epigenetic cytosine modifications in mammals: 5mC, 5hmC, 5fC and 5caC. The biological effects of 5mC are well understood but the roles of the remaining modifications remain elusive. Experimental and computational studies suggest that a single epigenetic mark has little structural effect but six of them can radically change the structure of DNA to a new form, F-DNA. Investigating the collective effect of multiple epigenetic marks requires the ability to interrogate all possible combinations of epigenetic states (e...
September 25, 2017: Bioinformatics
https://www.readbyqxmd.com/read/29026078/deciphering-tal-effectors-for-5-methylcytosine-and-5-hydroxymethylcytosine-recognition
#14
Yuan Zhang, Lulu Liu, Shengjie Guo, Jinghui Song, Chenxu Zhu, Zongwei Yue, Wensheng Wei, Chengqi Yi
DNA recognition by transcription activator-like effector (TALE) proteins is mediated by tandem repeats that specify nucleotides through repeat-variable diresidues. These repeat-variable diresidues form direct and sequence-specific contacts to DNA bases; hence, TALE-DNA interaction is sensitive to DNA chemical modifications. Here we conduct a thorough investigation, covering all theoretical repeat-variable diresidue combinations, for their recognition capabilities for 5-methylcytosine and 5-hydroxymethylcytosine, two important epigenetic markers in higher eukaryotes...
October 12, 2017: Nature Communications
https://www.readbyqxmd.com/read/29020633/erasure-of-tet-oxidized-5-methylcytosine-by-a-srap-nuclease
#15
Soo-Mi Kweon, Bing Zhu, Yibu Chen, L Aravind, Shuang-Yong Xu, Douglas E Feldman
Enzymatic oxidation of 5-methylcytosine (5mC) in DNA by the Tet dioxygenases reprograms genome function in embryogenesis and postnatal development. Tet-oxidized derivatives of 5mC such as 5-hydroxymethylcytosine (5hmC) act as transient intermediates in DNA demethylation or persist as durable marks, yet how these alternative fates are specified at individual CpGs is not understood. Here, we report that the SOS response-associated peptidase (SRAP) domain protein Srap1, the mammalian ortholog of an ancient protein superfamily associated with DNA damage response operons in bacteria, binds to Tet-oxidized forms of 5mC in DNA and catalyzes turnover of these bases to unmodified cytosine by an autopeptidase-coupled nuclease...
October 10, 2017: Cell Reports
https://www.readbyqxmd.com/read/28993426/effect-of-diabetes-status-and-hyperglycemia-on-global-dna-methylation-and-hydroxymethylation
#16
Jairo Arturo Pinzón-Cortés, Angelina Perna-Chaux, Nicolás Steven Rojas-Villamizar, Angélica Díaz-Basabe, Diana Carolina Polanía-Villanueva, María Fernanda Jácome, Carlos Olimpo Mendivil, Helena Groot, Valeriano López-Segura
Type 2 diabetes mellitus (T2DM) is characterized by oxidative stress that could lead to chronic micro- and macrovascular complications. We hypothesized that some of the target organ damage is mediated by oxidative alterations in epigenetic mechanisms involving DNA methylation (5mC) and DNA hydroxymethylation (5hmC). We analyzed global DNA methylation and hydroxymethylation in peripheral blood cells in well-controlled and poorly controlled patients with T2DM and compared them with healthy controls. We also analyzed microarrays of DNA methylation and gene expression of other important tissues in the context of diabetes from the GEO database repository and then compared these results with our experimental gene expression data...
November 2017: Endocrine Connections
https://www.readbyqxmd.com/read/28973458/tet2-and-tdg-mediated-changes-are-required-for-the-acquisition-of-distinct-histone-modifications-in-divergent-terminal-differentiation-of-myeloid-cells
#17
Antonio Garcia-Gomez, Tianlu Li, Martin Kerick, Francesc Català-Moll, Natalia R Comet, Javier Rodríguez-Ubreva, Lorenzo de la Rica, Miguel R Branco, Javier Martín, Esteban Ballestar
The plasticity of myeloid cells is illustrated by a diversity of functions including their role as effectors of innate immunity as macrophages (MACs) and bone remodelling as osteoclasts (OCs). TET2, a methylcytosine dioxygenase highly expressed in these cells and frequently mutated in myeloid leukemias, may be a key contributor to this plasticity. Through transcriptomic and epigenomic analyses, we investigated 5-methylcytosine (5mC), 5-hydroxymethylcytosine (5hmC) and gene expression changes in two divergent terminal myeloid differentiation processes, namely MAC and OC differentiation...
September 29, 2017: Nucleic Acids Research
https://www.readbyqxmd.com/read/28945496/mouse-olfactory-bulb-methylome-and-hydroxymethylome-maps-reveal-noncanonical-active-turnover-of-dna-methylation
#18
Qin Ma, Huan Lu, Ziying Xu, Yuanyuan Zhou, Weimin Ci
Hydroxylation of 5-methylcytosine (5mC) to 5-hydroxymethylcytosine (5hmC) by TET enzymes presents a particular regulatory mechanism in the mammalian brain. However, although methylation and hydroxymethylation of cytosines in non-CpG contexts have been reported, these mechanisms remain poorly understood. Here, we applied TAB-seq and oxBS-seq selectively to detect 5hmC and 5mC at base resolution in olfactory bulb derived from female mice. We found that active turnover of 5mC to 5hmC occurred in both CpG and non-CpG contexts...
August 2017: Epigenetics: Official Journal of the DNA Methylation Society
https://www.readbyqxmd.com/read/28940661/dna-methylation-in-embryo-development-epigenetic-impact-of-art-assisted-reproductive-technologies
#19
REVIEW
Sebastian Canovas, Pablo J Ross, Gavin Kelsey, Pilar Coy
DNA methylation can be considered a component of epigenetic memory with a critical role during embryo development, and which undergoes dramatic reprogramming after fertilization. Though it has been a focus of research for many years, the reprogramming mechanism is still not fully understood. Recent results suggest that absence of maintenance at DNA replication is a major factor, and that there is an unexpected role for TET3-mediated oxidation of 5mC to 5hmC in guarding against de novo methylation. Base-resolution and genome-wide profiling methods are enabling more comprehensive assessments of the extent to which ART might impair DNA methylation reprogramming, and which sequence elements are most vulnerable...
November 2017: BioEssays: News and Reviews in Molecular, Cellular and Developmental Biology
https://www.readbyqxmd.com/read/28934725/prenatal-exposure-to-mercury-associations-with-global-dna-methylation-and-hydroxymethylation-in-cord-blood-and-in-childhood
#20
Andres Cardenas, Sheryl L Rifas-Shiman, Lode Godderis, Radu-Corneliu Duca, Ana Navas-Acien, Augusto A Litonjua, Dawn L DeMeo, Kasey J Brennan, Chitra J Amarasiriwardena, Marie-France Hivert, Matthew W Gillman, Emily Oken, Andrea A Baccarelli
BACKGROUND: Mercury is a global pollutant, and prenatal exposure is associated with adverse health effects. To date, no studies have evaluated the association between prenatal mercury exposure and DNA hydroxymethylation, an epigenetic modification important for tissue differentiation and embryonic development. OBJECTIVES: We sought to evaluate the association between prenatal mercury exposure and offspring global DNA methylation and hydroxymethylation at birth and test for persistence of the association in childhood...
August 29, 2017: Environmental Health Perspectives
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