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active DNA demethylation

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
Yue Guo, Renyi Wu, John M Gaspar, Davit Sargsyan, Zheng-Yuan Su, Chengyue Zhang, Linbo Gao, David Cheng, Wenji Li, Chao Wang, Ran Yin, Mingzhu Fang, Michael P Verzi, Ronald P Hart, Ah-Ng Kong
Inflammation is highly associated with colon carcinogenesis. Epigenetic mechanisms could play an important role in the initiation and progression of colon cancer. Curcumin, a dietary phytochemical, shows promising effects in suppressing colitis-associated colon cancer in AOM-DSS mice. However, the potential epigenetic mechanisms of curcumin in colon cancer remain unknown. In this study, the anti-cancer effect of curcumin in suppressing colon cancer in an 18-week AOM-DSS colon cancer mouse model was confirmed...
March 14, 2018: Carcinogenesis
Ying Gan, Wanru Ma, Xiuhong Wang, Juanli Qiao, Baozhen Zhang, Chenghua Cui, Zhaojun Liu, Dajun Deng
Objective: To investigate the relationship between the transcription of ANRIL , P15 , P14 and P16 at the same locus and the regulation mechanism of ANRIL . Methods: Publicly available database of Cancer Cell Line Encyclopedia (CCLE) was used in bioinformatic analyses. Methylation of CpG islands was detected by denaturing high performance liquid chromatography (DHPLC). Gene transcript levels were determined using quantitative real-time polymerase chain reaction (qRT-PCR) assays...
February 2018: Chinese Journal of Cancer Research, Chung-kuo Yen Cheng Yen Chiu
Miguel Fontecha-Barriuso, Diego Martin-Sanchez, Olga Ruiz-Andres, Jonay Poveda, Maria Dolores Sanchez-Niño, Lara Valiño-Rivas, Marta Ruiz-Ortega, Alberto Ortiz, Ana Belén Sanz
Epigenetics refers to heritable changes in gene expression patterns not caused by an altered nucleotide sequence, and includes non-coding RNAs and covalent modifications of DNA and histones. This review focuses on functional evidence for the involvement of DNA and histone epigenetic modifications in the pathogenesis of kidney disease and the potential therapeutic implications. There is evidence of activation of epigenetic regulatory mechanisms in acute kidney injury (AKI), chronic kidney disease (CKD) and the AKI-to-CKD transition of diverse aetiologies, including ischaemia-reperfusion injury, nephrotoxicity, ureteral obstruction, diabetes, glomerulonephritis and polycystic kidney disease...
March 9, 2018: Nephrology, Dialysis, Transplantation
Hisashi Wada, Nighat Yasmin, Kiyokazu Kakugawa, Michiko Ohno-Oishi, Sebastian Nieke, Chizuko Miyamoto, Sawako Muroi, Ichiro Taniuchi
During differentiation of CD4+ CD8+ double-positive (DP) thymocytes into the CD4- CD8+ single-positive (CD8SP) thymocytes committed to the cytotoxic T cell lineage, Cd8a transcription is temporally terminated after positive selection and is subsequently reinitiated, a process known as coreceptor reversal. Despite the identification of a transcriptional enhancer in the Cd8a gene that directs reporter transgene expression specifically in CD8SP thymocytes, the molecular mechanisms controlling reactivation of the Cd8a gene are not fully understood...
March 12, 2018: Proceedings of the National Academy of Sciences of the United States of America
Linbo Gao, David Cheng, Jie Yang, Renyi Wu, Wenji Li, Ah-Ng Kong
Increasing evidence suggests that epigenetic aberrations contribute to the development and progression of cancers such as lung cancer. The promoter region of miR-9-3 was recently found to be hypermethylated in lung cancer, resulting in down-regulation of miR-9-3 and poor patient prognosis. Sulforaphane (SFN), a natural compound that is obtained from cruciferous vegetables, has potent anticancer activities. In this study, we aimed to investigate the effect of SFN on restoring the miR-9-3 level in lung cancer A549 cells through epigenetic regulation...
February 9, 2018: Journal of Nutritional Biochemistry
Hitoshi Itoh, Tsuyoshi Kadomatsu, Hironori Tanoue, Masaki Yugami, Keishi Miyata, Motoyoshi Endo, Jun Morinaga, Eisuke Kobayashi, Takeshi Miyamoto, Ryoma Kurahashi, Kazutoyo Terada, Hiroshi Mizuta, Yuichi Oike
The tumor microenvironment promotes epigenetic changes in tumor cells associated with tumor aggressiveness. Here we report that in primary tumor cells, increased interleukin-6 (IL-6) expression brought on by DNA demethylation of its promoter by ten-eleven translocation 2 (TET2) promotes lung metastasis in osteosarcoma (OS). Xenograft experiments show increased IL-6 expression and decreased methylation of its promoter in OS cells after implantation relative to before implantation. In addition, changes in IL-6 methylation and expression seen in OS cells at the primary site were maintained at the metastatic site...
March 8, 2018: Oncogene
Peter W S Hill, Harry G Leitch, Cristina E Requena, Zhiyi Sun, Rachel Amouroux, Monica Roman-Trufero, Malgorzata Borkowska, Jolyon Terragni, Romualdas Vaisvila, Sarah Linnett, Hakan Bagci, Gopuraja Dharmalingham, Vanja Haberle, Boris Lenhard, Yu Zheng, Sriharsa Pradhan, Petra Hajkova
Gametes are highly specialized cells that can give rise to the next generation through their ability to generate a totipotent zygote. In mice, germ cells are first specified in the developing embryo around embryonic day (E) 6.25 as primordial germ cells (PGCs). Following subsequent migration into the developing gonad, PGCs undergo a wave of extensive epigenetic reprogramming around E10.5-E11.5, including genome-wide loss of 5-methylcytosine. The underlying molecular mechanisms of this process have remained unclear, leading to our inability to recapitulate this step of germline development in vitro...
March 7, 2018: Nature
Alexei F Kirkin, Karine N Dzhandzhugazyan, Per Guldberg, Johnny Jon Fang, Rikke S Andersen, Christina Dahl, Jann Mortensen, Tim Lundby, Aase Wagner, Ian Law, Helle Broholm, Line Madsen, Christer Lundell-Ek, Morten F Gjerstorff, Henrik J Ditzel, Martin R Jensen, Walter Fischer
In cancer cells, cancer/testis (CT) antigens become epigenetically derepressed through DNA demethylation and constitute attractive targets for cancer immunotherapy. Here we report that activated CD4+ T helper cells treated with a DNA-demethylating agent express a broad repertoire of endogenous CT antigens and can be used as antigen-presenting cells to generate autologous cytotoxic T lymphocytes (CTLs) and natural killer cells. In vitro, activated CTLs induce HLA-restricted lysis of tumor cells of different histological types, as well as cells expressing single CT antigens...
March 6, 2018: Nature Communications
Ling Wang, Zongliang Jiang, Delun Huang, Jingyue Duan, Chang Huang, Shannon Sullivan, Kaneha Vali, Yexuan Yin, Ming Zhang, Jill Wegrzyn, Xiuchun Cindy Tian, Young Tang
BACKGROUND: The generation of induced pluripotent stem cells (iPSCs) has underdefined mechanisms. In addition, leukemia inhibitory factor (LIF) activated Janus kinase/signal transducer and activator of transcription 3 (JAK/STAT3) pathway is the master regulator for naïve-state pluripotency achievement and maintenance. However, the regulatory process to attain naïve pluripotent iPSCs is not well understood. RESULTS: We performed transcriptome analysis to dissect the genomic expression during mouse iPSC induction, with or without blocking the JAK/STAT3 activity...
March 6, 2018: BMC Genomics
Juan Fernando Paredes, Jose Fernando Lopez-Olmeda, Jose A Muñoz-Cueto, F Sánchez-Vázquez
This research aimed at investigating the light synchronization and endogenous origin of daily expression rhythms of eight key genes involved in epigenetic mechanisms (DNA methylation and demethylation) in zebrafish gonads. To this end, 84 zebrafish were distributed into six tanks, each one containing 14 fish (7 males and 7 females). Animals were subjected to 12 h light:12 h dark cycles (LD, lights on at ZT0 h) and fed randomly three times a day during the light phase. Locomotor activity rhythms were recorded in each tank for 20 days to test their synchronization to light...
March 6, 2018: Chronobiology International
Alexandre Mayran, Jacques Drouin
Pioneer transcription factors have the unique and important role of unmasking chromatin domains during development to allow the implementation of new cellular programs. Compared to those of other transcription factors, this activity implies that pioneer factors can recognize their target DNA sequences in so-called compacted or "closed" heterochromatin and can trigger remodeling of the adjoining chromatin landscape to provide accessibility to non-pioneer transcription factors. Recent studies identified several steps of pioneer action, namely rapid but weak initial binding to heterochromatin, stabilization of binding followed by chromatin opening and loss of CpG methylation that provides epigenetic memory...
March 5, 2018: Journal of Biological Chemistry
Hang-Soo Park, Hyosung Kwon, Jewon Yu, Yeonju Bae, Jae-Yong Park, Kyung-Ah Choi, Yeonho Choi, Sunghoi Hong
Direct conversion is a powerful approach to safely generate mature neural lineages with potential for treatment of neurological disorders. Astrocytes play a crucial role in neuronal homeostasis and their dysfunctions contribute to several neurodegenerative diseases. Using a single-cell approach for precision, we describe here a robust method using optimized DNA amounts for the direct conversion of mouse fibroblasts to astrocytes. Controlled amount of the reprogramming factors Oct4, Sox2, Klf4 and cMyc was directly delivered into a single fibroblast cell...
March 6, 2018: Artificial Cells, Nanomedicine, and Biotechnology
Yoshiyuki Seki
PR-domain containing protein 14 (PRDM14) is a site-specific DNA-binding protein and is required for establishment of pluripotency in embryonic stem cells (ESCs) and primordial germ cells (PGCs) in mice. DNA methylation status is regulated by the balance between de novo methylation and passive/active demethylation, and global DNA hypomethylation is closely associated with cellular pluripotency and totipotency. PRDM14 ensures hypomethylation in mouse ESCs and PGCs through two distinct layers, transcriptional repression of the DNA methyltransferases Dnmt3a/b/l and active demethylation by recruitment of TET proteins...
2018: Frontiers in Cell and Developmental Biology
Ao Chen, Xiaodong Chen, Shiqiang Cheng, Le Shu, Meiping Yan, Lun Yao, Binyu Wang, Shuguang Huang, Lei Zhou, Zaiqing Yang, Guoquan Liu
The fat mass and obesity-associated (FTO) gene is tightly related to body weight and fat mass, and plays a pivotal role in regulating lipid accumulation in hepatocytes. However, the mechanisms underlying its function are poorly understood. Sterol regulatory element binding protein-1c (SREBP1c) is a transcription factor that regulates lipogenesis. Cell death-inducing DFFA (DNA fragmentation factor-α)-like effector c (CIDEC) plays a crucial role in lipid droplets (LDs) size controlling and lipid accumulation...
February 24, 2018: Biochimica et Biophysica Acta
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
Andrea Coluccio, Gabriela Ecco, Julien Duc, Sandra Offner, Priscilla Turelli, Didier Trono
BACKGROUND: The KZFP/KAP1 (KRAB zinc finger proteins/KRAB-associated protein 1) system plays a central role in repressing transposable elements (TEs) and maintaining parent-of-origin DNA methylation at imprinting control regions (ICRs) during the wave of genome-wide reprogramming that precedes implantation. In naïve murine embryonic stem cells (mESCs), the genome is maintained highly hypomethylated by a combination of TET-mediated active demethylation and lack of de novo methylation, yet KAP1 is tethered by sequence-specific KZFPs to ICRs and TEs where it recruits histone and DNA methyltransferases to impose heterochromatin formation and DNA methylation...
February 26, 2018: Epigenetics & Chromatin
Mohammad Bozlur Rahman, Karl Schellander, Núria Llamas Luceño, Ann Van Soom
Currently, the world is facing the negative impact of global warming on all living beings. Adverse effects of global warming are also becoming obvious in dairy cattle breeding. In dairy bulls, low fertility has frequently been reported during summer season especially in tropical or subtropical conditions. Typically, spermatozoa at post-meiotic stages of development are more susceptible to heat stress. During this period extensive incorporation of histone modifications and hyperacetylation turns the chromatin into an unstable conformation...
February 12, 2018: Theriogenology
Yihong Li, Dun Liu, Zhiming Li, Xinhua Zhang, Yuhua Ye, Qifa Liu, Jie Shen, Zhi Chen, Huajie Huang, Yunhao Liang, Xu Han, Jing Liu, Xiuli An, Narla Mohandas, Xiangmin Xu
Erythroid Krüppel-like factor (EKLF/KLF1) is an erythroid-specific transcription factor whose activity is essential for erythropoiesis. The underlying mechanisms for EKLF specifically restricted to erythroid cells are of great interest but remain incompletely understood. To explore the epigenetic regulation of EKLF expression by promoter DNA methylation, we investigated the methylation status of the EKLF promoter and EKLF gene expression from a panel of human tissues. We observed that erythroid-specific hypomethylation of the EKLF promoter in adult erythroid cells was positively associated with EKLF expression...
February 15, 2018: Blood Cells, Molecules & Diseases
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
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