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Angad P Mehta, Han Li, Sean A Reed, Lubica Supekova, Tsotne Javahishvili, Peter G Schultz
Several modified bases have been observed in the genomic DNA of bacteriophages, prokaryotes, and eukaryotes that play a role in restriction systems and/or epigenetic regulation. In our efforts to understand the consequences of replacing a large fraction of a canonical nucleoside with a modified nucleoside, we previously replaced around 75% of thymidine (T) with 5'-hydroxymethyl-2'-deoxyuridine (5hmU) in the Escherichia coli genome. In this study, we engineered the pyrimidine nucleotide biosynthetic pathway using T4 bacteriophage genes to achieve approximately 63% replacement of 2'-deoxycytidine (dC) with 5-hydroxymethyl-2'-deoxycytidine (5hmC) in the E...
October 20, 2016: Journal of the American Chemical Society
Huarui Lu, Sweta Bhoopatiraju, Hongbo Wang, Nolan P Schmitz, Xiaohong Wang, Matthew J Freeman, Colleen L Forster, Michael R Verneris, Michael A Linden, Timothy C Hallstrom
Ubiquitin-like with PHD and ring finger domains 2 (UHRF2) binds to 5-hydroxymethylcytosine (5hmC), a DNA base involved in tissue development, but it is unknown how their distribution compares with each other in normal and malignant human tissues. We used IHC on human tumor specimens (160 from 19 tumor types) or normal tissue to determine the expression and distribution of UHRF2, Ki-67, and 5hmC. We also examined UHRF2 expression in cord blood progenitors and compared its expression to methylation status in 6 leukemia cell lines and 15 primary human leukemias...
October 12, 2016: Oncotarget
Xin Li, Yun Liu, Tal Salz, Kasper D Hansen, Andrew P Feinberg
DNA methylation at the 5-postion of cytosine (5mC) is an epigenetic modification that regulates gene expression and cellular plasticity in development and disease. The ten-eleven translocation (TET) gene family oxidizes 5mC to 5-hydroxymethylcytosine (5hmC), providing an active mechanism for DNA demethylation, and may also provide its own regulatory function. Here we applied oxidative bisulfite sequencing to generate whole-genome DNA methylation and hydroxymethylation maps at single-base resolution in paired human liver and lung normal and cancer...
October 13, 2016: Genome Research
Moshe Szyf
5'-hydroxymethylcytosine (5hmC) is a variant of the common covalent epigenetic modification of DNA 5'-methylcytosine (5mC). Although the presence of this modified base in mammalian DNA has been recognized for several decades, it has recently gained center stage as a suspected intermediate in enzymatic active demethylation of 5mC. The role of 5hmC remains elusive in spite of a large body of studies. It is proposed that 5hmC is a variant of the 5mC epigenetic signal and is involved in epigenetic regulation of gene function...
October 13, 2016: Epigenomics
Timothy Alexander Hore, Ferdinand von Meyenn, Mirunalini Ravichandran, Martin Bachman, Gabriella Ficz, David Oxley, Fátima Santos, Shankar Balasubramanian, Tomasz P Jurkowski, Wolf Reik
Epigenetic memory, in particular DNA methylation, is established during development in differentiating cells and must be erased to create naïve (induced) pluripotent stem cells. The ten-eleven translocation (TET) enzymes can catalyze the oxidation of 5-methylcytosine (5mC) to 5-hydroxymethylcytosine (5hmC) and further oxidized derivatives, thereby actively removing this memory. Nevertheless, the mechanism by which the TET enzymes are regulated, and the extent to which they can be manipulated, are poorly understood...
October 11, 2016: Proceedings of the National Academy of Sciences of the United States of America
Miho M Suzuki, Tomoko Mori, Noriyuki Satoh
The initiation of embryonic gene expression in ascidian embryos appears to be tightly regulated by the number of DNA replication cycles. DNA methylation is thought to contribute to the clock mechanism that counts the rounds of DNA replication. We used mass spectrometry and whole genome bisulfite sequencing to characterize DNA methylation changes that occur in early developmental stages of the ascidian, Ciona intestinalis. We found that global DNA methylation in early Ciona development was static, and a base-wise comparison between the genomes of consecutive developmental stages found no DNA demethylation that was related to zygotic gene activation...
October 5, 2016: Genomics
Di Liu, Chao Zhao, Hailin Wang
The detection of 5-hydroxymethylcytosine (5hmC), a newly recognized epigenetic mark, is essential to its functional study. Here, an efficient and simple two-step-amplification method to detect 5hmC mediated by glucosylation is reported, which combines rolling circle amplification (RCA) and a quantitative polymerase chain reaction (qPCR). In the first step RCA, the glucosylated 5hmC (5ghmC), but not 5hmC, 5-methylcytosine (5mC) or cytosine (C) bases, could directly and specifically inhibit the activity of phi29 DNA polymerase, resulting in less RCA product compared to that using C-/5mC-/5hmC-containing templates...
2016: Analytical Sciences: the International Journal of the Japan Society for Analytical Chemistry
Yue Ma, Hualin Fu, Chunlei Zhang, Shangli Cheng, Jie Gao, Zhen Wang, Weilin Jin, João Conde, Daxiang Cui
Epigenetic modifications sit 'on top of' the genome and influence DNA transcription, which can force a significant impact on cellular behavior and phenotype and, consequently human development and disease. Conventional methods for evaluating epigenetic modifications have inherent limitations and, hence, new methods based on nanoscale devices are needed. Here, we found that antioxidant (glutathione) chiral gold nanoclusters induce a decrease of 5-hydroxymethylcytosine (5hmC), which is an important epigenetic marker that associates with gene transcription regulation...
2016: Scientific Reports
Jie Zhao, Xin-Long Ma, Jian-Xiong Ma, Lei Sun, Bin Lu, Ying Wang, Guo-Sheng Xing, Yan Wang, Ben-Chao Dong, Li-Yan Xu, Ming-Jie Kuang, Lin Fu, Hao-Hao Bai, Yue Ma, Wei-Lin Jin
Steroid-associated osteonecrosis (SAON) is one of the common complications of clinical glucocorticoid (GC) administration, with osteocyte apoptosis appearing as the primary histopathological lesion. However, the precise mechanism underlying SAON remains unknown. Epigenetic modification may be a major cause of SAON. Recently, cumulative research revealed that Ten-Eleven Translocation (TET) proteins can catalyze the conversion of 5-methylcytosine (5mC) to 5-hydroxymethylcytosine (5hmC) and then alter the epigenetic state of DNA...
September 13, 2016: Journal of Bone and Mineral Research: the Official Journal of the American Society for Bone and Mineral Research
Joseph Hargan-Calvopina, Sara Taylor, Helene Cook, Zhongxun Hu, Serena A Lee, Ming-Ren Yen, Yih-Shien Chiang, Pao-Yang Chen, Amander T Clark
Remodeling DNA methylation in mammalian genomes can be global, as seen in preimplantation embryos and primordial germ cells (PGCs), or locus specific, which can regulate neighboring gene expression. In PGCs, global and locus-specific DNA demethylation occur in sequential stages, with an initial global decrease in methylated cytosines (stage I) followed by a Tet methylcytosine dioxygenase (Tet)-dependent decrease in methylated cytosines that act at imprinting control regions (ICRs) and meiotic genes (stage II)...
October 10, 2016: Developmental Cell
Sam T Romaine, Peter Wells-Jordan, Tracey de Haro, Avni Dave-Thakrar, Joanna North, James H Pringle, Gerald Saldanha
Melanoma is an aggressive cancer. Outcomes can vary significantly for lesions within the same pathological stage - a problem of increasing relevance with the promise of adjuvant treatments on the basis of immune checkpoint modulators and targeted therapies. The use of a panel of prognostic molecular biomarkers as an adjunct to stage represents a possible solution. Immunohistochemistry-based biomarkers offer greater potential for translation into clinical practice than biomarkers utilizing more complex methods...
September 3, 2016: Melanoma Research
Fleur A D Leenen, Claude P Muller, Jonathan D Turner
DNA methylation, through 5-methyl- and 5-hydroxymethylcytosine (5mC and 5hmC), is considered to be one of the principal interfaces between the genome and our environment, and it helps explain phenotypic variations in human populations. Initial reports of large differences in methylation level in genomic regulatory regions, coupled with clear gene expression data in both imprinted genes and malignant diseases, provided easily dissected molecular mechanisms for switching genes on or off. However, a more subtle process is becoming evident, where small (<10 %) changes to intermediate methylation levels are associated with complex disease phenotypes...
2016: Clinical Epigenetics
Rustam Esanov, Nadja S Andrade, Sarah Bennison, Claes Wahlestedt, Zane Zeier
Fragile X syndrome (FXS) results from a repeat expansion mutation near the FMR1 gene promoter and is the most common form of heritable intellectual disability and autism. Full mutations larger than 200 CGG repeats trigger FMR1 heterochromatinization and loss of gene expression, which is primarily responsible for the pathological features of FXS . In contrast, smaller pre-mutations of 55-200 CGG are associated with FMR1 overexpression and Fragile X-associated tremor/ataxia syndrome (FXTAS), a late-onset neurodegenerative condition...
September 5, 2016: Human Molecular Genetics
Tarmo Äijö, Xiaojing Yue, Anjana Rao, Harri Lähdesmäki
MOTIVATION: 5-methylcytosine (5mC) is a widely studied epigenetic modification of DNA. The ten-eleven translocation (TET) dioxygenases oxidize 5mC into oxidized methylcytosines (oxi-mCs): 5-hydroxymethylcytosine (5hmC), 5-formylcytosine (5fC) and 5-carboxylcytosine (5caC). DNA methylation modifications have multiple functions. For example, 5mC is shown to be associated with diseases and oxi-mC species are reported to have a role in active DNA demethylation through 5mC oxidation and DNA repair, among others, but the detailed mechanisms are poorly understood...
September 1, 2016: Bioinformatics
Elisabetta Valentini, Michele Zampieri, Marco Malavolta, Maria Giulia Bacalini, Roberta Calabrese, Tiziana Guastafierro, Anna Reale, Claudio Franceschi, Antti Hervonen, Bernhard Koller, Jürgen Bernhardt, P Eline Slagboom, Olivier Toussaint, Ewa Sikora, Efstathios S Gonos, Nicolle Breusing, Tilman Grune, Eugène Jansen, Martijn E T Dollé, María Moreno-Villanueva, Thilo Sindlinger, Alexander Bürkle, Fabio Ciccarone, Paola Caiafa
Gradual changes in the DNA methylation landscape occur throughout aging virtually in all human tissues. A widespread reduction of 5-methylcytosine (5mC), associated with highly reproducible site-specific hypermethylation, characterizes the genome in aging. Therefore, an equilibrium seems to exist between general and directional deregulating events concerning DNA methylation controllers, which may underpin the age-related epigenetic changes. In this context, 5mC-hydroxylases (TET enzymes) are new potential players...
August 29, 2016: Aging
Abdulkadir Abakir, Lee Wheldon, Andrew D Johnson, Patrick Laurent, Alexey Ruzov
Methylation of cytosine bases (5-methylcytosine, 5mC) occurring in vertebrate genomes is usually associated with transcriptional silencing. 5-hydroxylmethylcytosine (5hmC), 5-formylcytosine (5fC), and 5-carboxylcytosine (5caC) are the recently discovered modified cytosine bases produced by enzymatic oxidation of 5mC, whose biological functions remain relatively obscure. A number of approaches ranging from biochemical to antibody based techniques have been employed to study the genomic distribution and global content of these modifications in various biological systems...
2016: Journal of Visualized Experiments: JoVE
Feng C Zhou, Marisol Resendiz, Chiao-Ling Lo, Yuanyuan Chen
Global DNA de-methylation is thought to occur only during pre-implantation and gametogenesis in mammals. Scalable, cell-wide de-methylation has not been demonstrated beyond totipotent stages. Here, we observed a large scale de-methylation and subsequent re-methylation (CDR) (including 5-methylcytosine (5mC) and 5-hydroxylmethylcytosine (5hmC)) in post-mitotic cerebellar Purkinje cells (PC) through the course of normal development. Through single cell immuno-identification and cell-specific quantitative methylation assays, we demonstrate that the CDR event is an intrinsically scheduled program, occurring in nearly every PC...
2016: PloS One
Xiaoxiao Hou, Jun Liu, Zhiren Zhang, Yanhui Zhai, Yutian Wang, Zhengzhu Wang, Bo Tang, Xueming Zhang, Liguang Sun, Ziyi Li
DNA methylation and histone modification play important roles in the development of mammalian embryos. Cytochalasin B (CB) is an actin polymerization inhibitor that can significantly affect cell activity and is often used in studies concerning cytology. In recent years, CB is also commonly being used in in vitro experiments on mammalian embryos, but few studies have addressed the effect of CB on the epigenetic modification of embryonic development, and the mechanism underlying this process is also unknown. This study was conducted to investigate the effects of CB on DNA methylation and histone modification in the development of parthenogenetically activated porcine embryos...
November 2016: Reproduction: the Official Journal of the Society for the Study of Fertility
Ligia A Papale, Sisi Li, Andy Madrid, Qi Zhang, Li Chen, Pankaj Chopra, Peng Jin, Sündüz Keleş, Reid S Alisch
Environmental stress is among the most important contributors to increased susceptibility to develop psychiatric disorders. While it is well known that acute environmental stress alters gene expression, the molecular mechanisms underlying these changes remain largely unknown. 5-hydroxymethylcytosine (5hmC) is a novel environmentally sensitive epigenetic modification that is highly enriched in neurons and is associated with active neuronal transcription. Recently, we reported a genome-wide disruption of hippocampal 5hmC in male mice following acute stress that was correlated to altered transcript levels of genes in known stress related pathways...
August 26, 2016: Neurobiology of Disease
Minmin Liu, Hitoshi Ohtani, Wanding Zhou, Andreas Due Ørskov, Jessica Charlet, Yang W Zhang, Hui Shen, Stephen B Baylin, Gangning Liang, Kirsten Grønbæk, Peter A Jones
Vitamin C deficiency is found in patients with cancer and might complicate various therapy paradigms. Here we show how this deficiency may influence the use of DNA methyltransferase inhibitors (DNMTis) for treatment of hematological neoplasias. In vitro, when vitamin C is added at physiological levels to low doses of the DNMTi 5-aza-2'-deoxycytidine (5-aza-CdR), there is a synergistic inhibition of cancer-cell proliferation and increased apoptosis. These effects are associated with enhanced immune signals including increased expression of bidirectionally transcribed endogenous retrovirus (ERV) transcripts, increased cytosolic dsRNA, and activation of an IFN-inducing cellular response...
September 13, 2016: Proceedings of the National Academy of Sciences of the United States of America
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