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Ya-Wen Cheng, Chia-Jung Chou, Pei-Ming Yang
DNA 5-methylcytosine (5-mC) methylation, a key epigenetic mark, is critical for biological and pathological processes. Aberrant DNA methylation occurs in all tumor types and correlates with tumor suppressor gene silencing. DNA methylation is thought to be very stable, and active DNA demethylation remains a long-standing enigma. Recently, the ten-eleven translocation (TET) family of oxygenases are found to oxidize 5-mC to 5-hydroxymethylcytosine (5-hmC), which is prerequisite for active DNA demethylation. Both TET1 expression and global 5-hmC content are significantly reduced in colorectal cancer (CRC), the top leading cause of cancer-related death in the world...
March 2018: Surgical Oncology
Tie Li, Christopher D Cox, Byram Ozer, Nhung T Nguyen, Huytram N Nguyen, Thomas J Lai, Sichen Li, Fei Liu, Harley I Kornblum, Linda M Liau, Phioanh Leia Nghiemphu, Timothy F Cloughesy, Albert Lai
Mutant isocitrate dehydrogenase (IDH) 1/2 converts α-ketoglutarate (α-KG) to D-2 hydroxyglutarate (D-2-HG), a putative oncometabolite that can inhibit α-KG dependent enzymes, including ten-eleven translocation methylcytosine dioxygenase (TET) DNA demethylases. We recently established that miRNAs are components of the IDH1 mutant-associated glioma CpG island methylator phenotype (G-CIMP), and specifically identified MIR148A as a tumor-suppressive miRNA within G-CIMP. However, the precise mechanism by which mutant IDH induces hypermethylation of MIR148A and other G-CIMP promoters remains to be elucidated...
March 15, 2018: Molecular Cancer Research: MCR
Xin Wang, Xinxin Liu, Xiaoru Duan, Ke Zhu, Song Zhang, Lu Gan, Nian Liu, Himanshu Jaypaul, Johanna T Makamure, Zhangyin Ming, Hongxiang Chen
Epigenetics plays an important role in the development and progression of many diseases. There is increasing evidence for the importance of epigenetic modifications in the progression of psoriasis. The aim of this study was to examine the role and potential mechanism of action of 5-hydroxymethylcytosine (5-hmC) and ten-eleven translocation-2 (TET2) in psoriasiform dermatitis. Immunohistochemical staining was performed on psoriasis patients and healthy controls. Topical application of imiquimod cream to the dorsal skin of mice was used to induce psoriasiform dermatitis...
March 15, 2018: Acta Dermato-venereologica
Ruichuan Yin, Jiezhen Mo, Jiayin Dai, Hailin Wang
Nickel is found widely in the environment. It is an essential microelement but also toxic. However, nickel displays only weak genotoxicity and mutagenicity. Exploration of the epigenetic toxicity of nickel is extremely interesting. Iron(ii)- and 2-oxoglutarate-dependent Tet dioxygenases are a class of epigenetic enzymes that catalyze the oxidation of DNA 5-methylcytosine (5mC). Thus, they are critical for DNA demethylation and, importantly, are involved with nuclear reprogramming, embryonic development, and regulation of gene expression...
March 14, 2018: Metallomics: Integrated Biometal Science
Anjing Zhong, Yiping Tian, Honghe Zhang, Maode Lai
METHODS: A total of 71 cases of colorectal carcinoma with hepatic metastasis were enrolled from the Department of Pathology of SIR RUN RUN SHAW Hospital. Paired primary tumors, hepatic metastases, and normal mucosa samples were collected from formalin-fixed paraffin-embedded tissues by manual macrodissection. And global levels of DNA methylation and hydroxymethylation in these tissues, measured by an ELISA-like microplate-based colorimetric methods. The immunohistochemical expression of 5-methylcytosine and 5-hydroxymethylcytosine were analyzed also...
March 12, 2018: Journal of Surgical Oncology
R Murín, M Abdalla, N Murínová, J Hatok, D Dobrota
The fundamental biochemical processes of 5-methylcytosine (5-mC) synthesis, maintenance, conversion and removal determine the time and spatial pattern of DNA methylation. This has a strong effect on a plethora of physiological aspects of cellular metabolism. While the presence of 5-mC within the promoter region can silence gene expression, its derivative - 5-hydroxymethylcytosine exerts an opposite effect. Dysregulations in the metabolism of 5-mC lead to an altered DNA methylation pattern which is linked with a disrupted epigenome, and are considered to play a significant part in the etiology of several human diseases...
March 12, 2018: Physiological Research
W X Li, Q W Ma, F Y Zeng
Objective: To study the function of ten-eleven translocation 2 (Tet2) in γ globin gene expression in patients with β- thalassemia. Methods: Gamma globin expression was induced by 5-azacytidine and Tet2 gene expression was knocked down by short hairpin RNA (shRNA) in a human immortalized myelogenous leukemia K562 cell line. The global 5-hydroxymethylcytosine (5hmC) level was measured by an ELISA kit. 5hmC level of γ globin gene was quantified by sulfite sequencing. The mRNA level of Tet2, γ globin, and related transcription factors Nfe4 and Klf1 were quantified by real-time PCR...
March 1, 2018: Zhonghua Nei Ke za Zhi [Chinese Journal of Internal Medicine]
Yimin Zhu, Hanlin Lu, Dandan Zhang, Meiyan Li, Xiaohui Sun, Ledong Wan, Dan Yu, Yiping Tian, Hongchuan Jin, Aifen Lin, Fei Gao, Maode Lai
Background: DNA methylation is an important epigenetic modification, associated with gene expression. 5-Methylcytosine and 5-hydroxymethylcytosine are two epigenetic hallmarks that maintain the equilibrium of epigenetic reprogramming. Disequilibrium in genomic methylation leads to carcinogenesis. The purpose of this study was to elucidate the epigenetic mechanisms of DNA methylation and hydroxymethylation in the carcinogenesis of colorectal cancer. Methods: Genome-wide patterns of DNA methylation and hydroxymethylation in six paired colorectal tumor tissues and corresponding normal tissues were determined using immunoprecipitation and sequencing...
2018: Clinical Epigenetics
Kohtaro Morita, Mikiko Tokoro, Yuki Hatanaka, Chika Higuchi, Haruka Ikegami, Kouhei Nagai, Masayuki Anzai, Hiromi Kato, Tasuku Mitani, Yoshitomo Taguchi, Kazuo Yamagata, Yoshihiko Hosoi, Kei Miyamoto, Kazuya Matsumoto
Antioxidant mechanisms to adequately moderate levels of endogenous reactive oxygen species (ROS) are important for oocytes and embryos to obtain and maintain developmental competence, respectively. Immediately after fertilization, ROS levels in zygotes are elevated but the antioxidant mechanisms during the maternal-to-zygotic transition (MZT) are not well understood. First, we identified peroxiredoxin 1 (PRDX1) and PRDX2 by proteomics analysis as two of the most abundant endogenous antioxidant enzymes eliminating hydrogen peroxide (H2 O2 )...
March 2, 2018: Journal of Reproduction and Development
Andy Madrid, Pankaj Chopra, Reid S Alisch
Human evolution from non-human primates has seen substantial change in the central nervous system, with the molecular mechanisms underlying human brain evolution remaining largely unknown. Methylation of cytosine at the fifth carbon (5-methylcytosine; 5 mC) is an essential epigenetic mark linked to neurodevelopment, as well as neurological disease. The emergence of another modified form of cytosine (5-hydroxymethylcytosine; 5 hmC) that is enriched in the brain further substantiates a role for these epigenetic marks in neurodevelopment, yet little is known about the evolutionary importance of these marks in brain development...
2018: Frontiers in Molecular Neuroscience
Diana Guallar, Xianju Bi, Jose Angel Pardavila, Xin Huang, Carmen Saenz, Xianle Shi, Hongwei Zhou, Francesco Faiola, Junjun Ding, Phensinee Haruehanroengra, Fan Yang, Dan Li, Carlos Sanchez-Priego, Arven Saunders, Feng Pan, Victor Julian Valdes, Kevin Kelley, Miguel G Blanco, Lingyi Chen, Huayan Wang, Jia Sheng, Mingjiang Xu, Miguel Fidalgo, Xiaohua Shen, Jianlong Wang
Ten-eleven translocation (TET) proteins play key roles in the regulation of DNA-methylation status by oxidizing 5-methylcytosine (5mC) to generate 5-hydroxymethylcytosine (5hmC), which can both serve as a stable epigenetic mark and participate in active demethylation. Unlike the other members of the TET family, TET2 does not contain a DNA-binding domain, and it remains unclear how it is recruited to chromatin. Here we show that TET2 is recruited by the RNA-binding protein Paraspeckle component 1 (PSPC1) through transcriptionally active loci, including endogenous retroviruses (ERVs) whose long terminal repeats (LTRs) have been co-opted by mammalian genomes as stage- and tissue-specific transcriptional regulatory modules...
February 26, 2018: Nature Genetics
Jinlu Xing, Yuejie Ai, Yang Liu, Jia Du, Weiqiang Chen, Zhanhui Lu, Xiangke Wang
Cytosine methylation and demethylation play crucial roles in understanding the genomic DNA expression regulation. The epigenetic modification of cytosine and its continuous oxidative products-the "new four bases of DNA" including 5-methylcytosine (5mC), 5-hydroxymethylcytosine (5hmC), 5-formylcytosine (5fC), 5-carboxylcytosine (5caC). However, compared to the abundant studies on the classical DNA bases, the photophysical and photochemical properties of those new bases have not yet aroused people's excessive attention...
February 22, 2018: Journal of Physical Chemistry. B
Geraldine Gontier, Manasi Iyer, Jeremy M Shea, Gregor Bieri, Elizabeth G Wheatley, Miguel Ramalho-Santos, Saul A Villeda
Restoring adult stem cell function provides an exciting approach for rejuvenating the aging brain. However, molecular mechanisms mediating neurogenic rejuvenation remain elusive. Here we report that the enzyme ten eleven translocation methylcytosine dioxygenase 2 (Tet2), which catalyzes the production of 5-hydroxymethylcytosine (5hmC), rescues age-related decline in adult neurogenesis and enhances cognition in mice. We detected a decrease in Tet2 expression and 5hmC levels in the aged hippocampus associated with adult neurogenesis...
February 20, 2018: Cell Reports
Longsen Han, Chao Ren, Ling Li, Xiaoyan Li, Juan Ge, Haichao Wang, Yi-Liang Miao, Xuejiang Guo, Kelle H Moley, Qiang Wang, Wenjie Shu
Maternal obesity can impair embryo development and offspring health, yet the mechanisms responsible remain poorly understood. In a high-fat diet (HFD)-based female mouse model of obesity, we identified a marked reduction of Stella (also known as DPPA3 or PGC7) protein in oocytes. Starting with this clue, we found that the establishment of pronuclear epigenetic asymmetry in zygotes from obese mice was severely disrupted, inducing the accumulation of maternal 5-hydroxymethylcytosine modifications and DNA lesions...
February 19, 2018: Nature Genetics
Jacob J Briedé, Lize Deferme, Jarno E J Wolters, Sandra M H Claessen, Twan van den Beucken, J Richard Wagner, Simone G van Breda, Jos C S Kleinjans
Regulation of DNA methylation plays a crucial role in biological processes and carcinogenesis. The formation of 5-hydroxymethylcytosine (5hmC) by oxidation of 5-methylcytosine (5mC) has been proposed as an intermediate of active demethylation. However, whether and how active demethylation is regulated by oxidative stress-related processes is not well understood. Here we investigated whether free oxygen radicals are capable of directly forming 5hmC and how this enhanced whole genome gene expression. We applied LC-MS/MS technology for the analysis of 5mC, 5hmC, 5-formylcytosine (5fC) and 5-hydroxymethyluracyl (5hmU) in HepG2 cells exposed to hydroxyl- and methyl radicals, formed by tert-butyl hydroperoxide (TBH) at multiple time points...
February 9, 2018: Toxicology in Vitro: An International Journal Published in Association with BIBRA
Wioletta K Glowacka, Harshika Jain, Makiko Okura, Abulizi Maimaitiming, Yasin Mamatjan, Romina Nejad, Hamza Farooq, Michael D Taylor, Kenneth Aldape, Paul Kongkham
Gliomas demonstrate epigenetic dysregulation exemplified by the Glioma CpG Island Methylator Phenotype (G-CIMP) seen in IDH1 mutant tumors. 5-Hydroxymethylcytosine (5hmC) is implicated in glioma pathogenesis; however, its role in IDH1 mutant gliomas is incompletely understood. To characterize 5hmC in IDH1 mutant gliomas further, we examine 5hmC in a cohort of IDH1 mutant and wild-type high-grade gliomas (HGG) using a quantitative locus-specific approach. Regions demonstrating high 5hmC abundance and differentially hydroxymethylated regions (DHMR) enrich for enhancers implicated in glioma pathogenesis...
February 10, 2018: Acta Neuropathologica
Hamid Hamzeiy, Doruk Savaş, Ceren Tunca, Nesli Ece Şen, Aslı Gündoğdu Eken, Irmak Şahbaz, Daniela Calini, Cinzia Tiloca, Nicola Ticozzi, Antonia Ratti, Vincenzo Silani, A Nazlı Başak
Adult-onset neurological disorders are caused and influenced by a multitude of different factors, including epigenetic modifications. Here, using an ELISA kit selected upon careful testing, we investigated global 5-methylcytosine (5-mC) levels in sporadic and familial amyotrophic lateral sclerosis (sALS and fALS), spinocerebellar ataxia types 1 and 2 (SCA1 and SCA2), Huntington's disease, Friedreich's ataxia, and myotonic dystrophy type 1. We report a significant elevation in global 5-mC levels of about 2-7% on average for sALS (p < 0...
February 9, 2018: Neuro-degenerative Diseases
Ling Shan, Hang-Yuan Guo, Corina N A M van den Heuvel, Joop van Heerikhuize, Judith R Homberg
AIMS: One potential risk factor for posttraumatic stress disorder (PTSD) involves the low activity (short; s) allelic variant of the serotonin transporter-linked polymorphic region (5-HTTLPR), possibly due to reduced prefrontal control over the amygdala. Evidence shows that DNA methylation/demethylation is crucial for fear extinction in these brain areas and is associated with neuronal activation marker c-Fos expression. We hypothesized that impaired fear extinction in serotonin transporter knockout (5-HTT-/- ) rats is related to changes in DNA (de) methylation and c-Fos expression in the prefrontal cortex (PFC) and/or amygdala...
February 9, 2018: CNS Neuroscience & Therapeutics
Ewelina Zarakowska, Jolanta Czerwinska, Agnieszka Tupalska, Matt J Yousefzadeh, Siobhán Q Gregg, Claudette M St Croix, Laura J Niedernhofer, Marek Foksinski, Daniel Gackowski, Anna Szpila, Marta Starczak, Barbara Tudek, Ryszard Olinski
5-Hydroxymethylcytosine and 5-formylcytosine are stable DNA base modifications generated from 5-methylcytosine by the ten-eleven translocation protein family that function as epigenetic markers. 5-Hydroxymethyluracil may also be generated from thymine by ten-eleven translocation enzymes. Here, we asked if these epigenetic changes accumulate in senescent cells, since they are thought to be inversely correlated with proliferation. Testing this in ERCC1-XPF-deficient cells and mice also enabled discovery if these DNA base changes are repaired by nucleotide excision repair...
February 3, 2018: Journals of Gerontology. Series A, Biological Sciences and Medical Sciences
Qianyun Deng, Wei Huang, Chunyan Peng, Jiajia Gao, Zuhua Li, Xueping Qiu, Na Yang, Bifeng Yuan, Fang Zheng
Background: Alterations in DNA methylation are demonstrated in atherosclerosis pathogenesis. However, changing rules of global DNA methylation and hydroxymethylation in peripheral blood leukocytes (PBLs) and different blood cell subtypes of coronary artery disease (CAD) patients are still inconclusive, and much less is known about mechanisms underlying. Results: We recruited 265 CAD patients and 270 healthy controls with genomic DNA from PBLs, of which 50 patients and 50 controls were randomly chosen with DNA from isolated neutrophils, lymphocytes and monocytes, and RNA from PBLs...
2018: Clinical Epigenetics
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