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DNA demethylation

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https://www.readbyqxmd.com/read/29456084/rescue-of-fragile-x-syndrome-neurons-by-dna-methylation-editing-of-the-fmr1-gene
#1
X Shawn Liu, Hao Wu, Marine Krzisch, Xuebing Wu, John Graef, Julien Muffat, Denes Hnisz, Charles H Li, Bingbing Yuan, Chuanyun Xu, Yun Li, Dan Vershkov, Angela Cacace, Richard A Young, Rudolf Jaenisch
Fragile X syndrome (FXS), the most common genetic form of intellectual disability in males, is caused by silencing of the FMR1 gene associated with hypermethylation of the CGG expansion mutation in the 5' UTR of FMR1 in FXS patients. Here, we applied recently developed DNA methylation editing tools to reverse this hypermethylation event. Targeted demethylation of the CGG expansion by dCas9-Tet1/single guide RNA (sgRNA) switched the heterochromatin status of the upstream FMR1 promoter to an active chromatin state, restoring a persistent expression of FMR1 in FXS iPSCs...
February 8, 2018: Cell
https://www.readbyqxmd.com/read/29455551/effects-of-5-aza-2-deoxycytidine-decitabine-on-gene-expression
#2
Ratnam S Seelan, Partha Mukhopadhyay, M Michele Pisano, Robert M Greene
5-Aza-2'-deoxycytidine (AzaD), also known as Decitabine, is a deoxycytidine analog that is typically used to activate methylated and silenced genes by promoter demethylation. However, a survey of the scientific literature indicates that promoter demethylation may not be the only (or, indeed, the major) mechanism by which AzaD affects gene expression. Regulation of gene expression by AzaD can occur in several ways, including some that are independent of DNA demethylation. Results from several studies indicate that the effect of AzaD on gene expression is highly context-dependent and can differ for the same gene under different environmental settings...
February 18, 2018: Drug Metabolism Reviews
https://www.readbyqxmd.com/read/29454856/nucleosidic-dna-demethylating-epigenetic-drugs-a-comprehensive-review-from-discovery-to-clinic
#3
REVIEW
Khushboo Agrawal, Viswanath Das, Pankhuri Vyas, Marián Hajdúch
DNA methylation plays a pivotal role in the etiology of cancer by mediating epigenetic silencing of cancer-related genes. Since the relationship between aberrant DNA methylation and cancer has been understood, there has been an explosion of research at developing anti-cancer therapies that work by inhibiting DNA methylation. From the discovery of first DNA hypomethylating drugs in the 1980s to recently discovered second generation pro-drugs, exceedingly large number of studies have been published that describe the DNA hypomethylation-based anti-neoplastic action of these drugs in various stages of the pre-clinical investigation and advanced stages of clinical development...
February 15, 2018: Pharmacology & Therapeutics
https://www.readbyqxmd.com/read/29453678/differential-expression-of-the-tweak-receptor-fn14-in-idh1-wild-type-and-mutant-gliomas
#4
David S Hersh, Sen Peng, Jimena G Dancy, Rebeca Galisteo, Jennifer M Eschbacher, Rudy J Castellani, Jonathan E Heath, Teklu Legesse, Anthony J Kim, Graeme F Woodworth, Nhan L Tran, Jeffrey A Winkles
The TNF receptor superfamily member Fn14 is overexpressed by many solid tumor types, including glioblastoma (GBM), the most common and lethal form of adult brain cancer. GBM is notable for a highly infiltrative growth pattern and several groups have reported that high Fn14 expression levels can increase tumor cell invasiveness. We reported previously that the mesenchymal and proneural GBM transcriptomic subtypes expressed the highest and lowest levels of Fn14 mRNA, respectively. Given the recent histopathological re-classification of human gliomas by the World Health Organization based on isocitrate dehydrogenase 1 (IDH1) gene mutation status, we extended this work by comparing Fn14 gene expression in IDH1 wild-type (WT) and mutant (R132H) gliomas and in cell lines engineered to overexpress the IDH1 R132H enzyme...
February 16, 2018: Journal of Neuro-oncology
https://www.readbyqxmd.com/read/29453320/methylation-of-the-hoxa10-promoter-directs-mir-196b-5p-dependent-cell-proliferation-and-invasion-of-gastric-cancer-cells
#5
Linlin Shao, Zheng Chen, Dunfa Peng, Mohammed Soutto, Shoumin Zhu, Andreia Bates, Shutian Zhang, Wael El-Rifai
The cross-talk between epigenetics and miRNA expression plays an important role in human tumorigenesis. Herein, we investigated the regulation and role of miR-196b-5p in gastric cancer. Using quantitative real-time RT-PCR, we demonstrate that miR-196b-5p is significantly overexpressed in human gastric cancer tissues (P<0.01). In addition, we also found that HOXA10, the host gene for miR-196b-5p, is overexpressed and positively correlated with miR-196b-5p expression levels (P<0.001). Quantitative pyrosequencing methylation analysis of HOXA10 promoter, demonstrated significantly lower levels of promoter DNA methylation of HOXA10 in gastric cancer samples, as compared to normal gastric mucosa samples (non-tumor control)...
February 16, 2018: Molecular Cancer Research: MCR
https://www.readbyqxmd.com/read/29447921/dna-demethylation-of-claudin-4-suppresses-migration-and-invasion-in-laryngeal-squamous-carcinoma-cells
#6
Yafang Liu, Kai Chang, Kexin Fu, Xinjie Dong, Xiaoshuai Chen, Jixuan Liu, Ni Cui, Jinsong Ni
Claudin-4 (CLDN4) is a member of the claudin transmembrane protein family, which consists of integral membrane proteins that are components of the epithelial cell tight junctions; these tight junctions regulate movement of solutes and ions through the paracellular space. CLDN4 is also a differentiation marker and is believed to indicate an epithelial phenotype. However, the role of CLDN4 in laryngeal squamous carcinoma is still unclear. Here, we showed that CLDN4 expression was down-regulated in laryngeal squamous carcinoma tissues and negatively correlated with Methyl-CpG-binding protein 2 (MeCP2)...
February 12, 2018: Human Pathology
https://www.readbyqxmd.com/read/29445424/promoter-methylation-of-dna-damage-repair-ddr-genes-in-human-tumor-entities-rbbp8-ctip-is-almost-exclusively-methylated-in-bladder-cancer
#7
Jolein Mijnes, Jürgen Veeck, Nadine T Gaisa, Eduard Burghardt, Tim C de Ruijter, Sonja Gostek, Edgar Dahl, David Pfister, Sebastian C Schmid, Ruth Knüchel, Michael Rose
Background: Genome-wide studies identified pan-cancer genes and shared biological networks affected by epigenetic dysregulation among diverse tumor entities. Here, we systematically screened for hypermethylation of DNA damage repair (DDR) genes in a comprehensive candidate-approach and exemplarily identify and validate candidate DDR genes as targets of epigenetic inactivation unique to bladder cancer (BLCA), which may serve as non-invasive biomarkers. Methods: Genome-wide DNA methylation datasets (2755 CpG probes of n = 7819 tumor and n = 659 normal samples) of the TCGA network covering 32 tumor entities were analyzed in silico for 177 DDR genes...
2018: Clinical Epigenetics
https://www.readbyqxmd.com/read/29444862/targeted-dna-demethylation-of-the-arabidopsis-genome-using-the-human-tet1-catalytic-domain
#8
Javier Gallego-Bartolomé, Jason Gardiner, Wanlu Liu, Ashot Papikian, Basudev Ghoshal, Hsuan Yu Kuo, Jenny Miao-Chi Zhao, David J Segal, Steven E Jacobsen
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...
February 14, 2018: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/29437831/lsd1-interacts-with-cmyb-to-demethylate-repressive-histone-marks-and-maintains-inner-ear-progenitor-identity
#9
Mohi Ahmed, Andrea Streit
During development, multipotent progenitor cells must maintain their identity while retaining the competence to respond to new signalling cues that drive cell fate decisions. This depends on both DNA-bound transcription factors and surrounding histone modifications. Here we identify the histone demethylase Lsd1 as a crucial component of the molecular machinery that preserves progenitor identity in the developing ear prior to lineage commitment. While Lsd1 is mainly associated with repressive complexes, we show that in ear precursors it is required to maintain active transcription of otic genes...
February 5, 2018: Development
https://www.readbyqxmd.com/read/29436620/highglucose-induces-podocyteepithelial%C3%A2-to%C3%A2-mesenchymal-transition-by-demethylation%C3%A2-mediated-enhancement-of-mmp9-expression
#10
Li Ling, Libo Chen, Changning Zhang, Shuyan Gui, Haiyan Zhao, Zhengzhang Li
Abnormal expression of matrix metalloproteinase 9 (MMP9) is correlated with podocyte epithelial-to---mesenchymal transition (EMT) in diabetic nephropathy (DN). However, the mechanisms underlying this process are not well defined. Site‑specific demethylation may sustain high expression levels of target genes. In the present study, in order to investigate the association between DNA demethylation of MMP9 promoter and podocyte EMT in DN, human podocytes were cultured in high‑glucose (HG) medium and a rat model of DN was established by intraperitoneal injection of streptozotocin (STZ) to determine whether site‑specific demethylation of the MMP9 promoter was involved in regulating podocyte EMT in DN...
February 2, 2018: Molecular Medicine Reports
https://www.readbyqxmd.com/read/29435941/the-mir-302-mediated-induction-of-pluripotent-stem-cells-ipsc-multiple-synergistic-reprogramming-mechanisms
#11
Shao-Yao Ying, William Fang, Shi-Lung Lin
Pluripotency represents a unique feature of embryonic stem cells (ESCs). To generate ESC-like-induced pluripotent stem cells (iPSCs) derived from somatic cells, the cell genome needs to be reset and reprogrammed to express the ESC-specific transcriptome. Numerous studies have shown that genomic DNA demethylation is required for epigenetic reprogramming of somatic cell nuclei to form iPSCs; yet, the mechanism remains largely unclear. In ESCs, the reprogramming process goes through two critical stages: germline and zygotic demethylation, both of which erase genomic DNA methylation sites and hence allow for different gene expression patterns to be reset into a pluripotent state...
2018: Methods in Molecular Biology
https://www.readbyqxmd.com/read/29434897/folate-deficiency-and-aberrant-dna-methylation-and-expression-of-fhit-gene-were-associated-with-cervical-pathogenesis
#12
Qiaoling Li, Ling Ding, Nan Jing, Chunliang Liu, Zuokai Yang, Fang Chen, Lifang Hou, Jintao Wang
Aberrant DNA methylation is a recognized feature in various types of human cancer, and folate has a vital role in the epigenetics of mammalian cells by supplying methyl groups for DNA methylation reactions. Fragile histidine triad (FHIT) is a tumor suppressor gene that is frequently silenced in cervical cancer (CC) and preneoplastic lesions. Promoter hypermethylation was previously observed in CC, and its epigenetic silencing has been observed at mRNA or protein levels. Changes in folate intake to modulate DNA methylation may be a mechanistic link to cancer, but this remains to be elucidated...
February 2018: Oncology Letters
https://www.readbyqxmd.com/read/29434893/bone-marrow-stromal-cells-enhance-the-survival-of-chronic-lymphocytic-leukemia-cells-by-regulating-hes-1-gene-expression-and-h3k27me3-demethylation
#13
Zhenshu Xu, Donglian Xiong, Jushun Zhang, Jingyan Zhang, Xiuli Chen, Zhizhe Chen, Rong Zhan
The majority of patients with chronic lymphocytic leukemia (CLL) are not cured by traditional chemotherapy. One possible explanation for this is that the microenvironment protects CLL cells from both spontaneous- and cytotoxic-mediated apoptosis. The present study was designed to investigate the mechanisms accounting for these effects, since this information is crucial to understanding CLL physiopathology and identifying potential treatment targets. The CLL cell line L1210 and primary CLL cells were cultured under different conditions: With serum, cyclophosphamide (CTX), or with monolayers and conditioned medium (CM) from the stromal cell line HESS-5...
February 2018: Oncology Letters
https://www.readbyqxmd.com/read/29434210/epigenetic-modulation-of-fgf21-in-the-perinatal-mouse-liver-ameliorates-diet-induced-obesity-in-adulthood
#14
Xunmei Yuan, Kazutaka Tsujimoto, Koshi Hashimoto, Kenichi Kawahori, Nozomi Hanzawa, Miho Hamaguchi, Takami Seki, Makiko Nawa, Tatsuya Ehara, Yohei Kitamura, Izuho Hatada, Morichika Konishi, Nobuyuki Itoh, Yoshimi Nakagawa, Hitoshi Shimano, Takako Takai-Igarashi, Yasutomi Kamei, Yoshihiro Ogawa
The nutritional environment to which animals are exposed in early life can lead to epigenetic changes in the genome that influence the risk of obesity in later life. Here, we demonstrate that the fibroblast growth factor-21 gene (Fgf21) is subject to peroxisome proliferator-activated receptor (PPAR) α-dependent DNA demethylation in the liver during the postnatal period. Reductions in Fgf21 methylation can be enhanced via pharmacologic activation of PPARα during the suckling period. We also reveal that the DNA methylation status of Fgf21, once established in early life, is relatively stable and persists into adulthood...
February 12, 2018: Nature Communications
https://www.readbyqxmd.com/read/29432895/a-cross-omics-approach-to-investigate-temporal-gene-expression-regulation-by-5-hydroxymethylcytosine-via-tbh-derived-oxidative-stress-showed-involvement-of-different-regulatory-kinases
#15
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
https://www.readbyqxmd.com/read/29430678/zebularine-treatment-is-associated-with-deletion-of-ft-b1-leading-to-an-increase-in-spikelet-number-in-bread-wheat
#16
E Jean Finnegan, Brett Ford, Xiaomei Wallace, Filomena Pettolino, Patrick T Griffin, Robert J Schmitz, Peng Zhang, Jose M Barrero, Matthew J Hayden, Scott A Boden, Colin A Cavanagh, Steve M Swain, Ben Trevaskis
The number of rachis nodes (spikelets) on a wheat spike is a component of grain yield that correlates with flowering time. The genetic basis regulating flowering in cereals is well understood, but there are reports that flowering time can be modified at high frequency by selective breeding, suggesting that it may be regulated by both epigenetic and genetic mechanisms. We investigated the role of DNA methylation in regulating spikelet number and flowering time by treating a semi-spring wheat with the demethylating agent, Zebularine...
February 10, 2018: Plant, Cell & Environment
https://www.readbyqxmd.com/read/29427306/impaired-fear-extinction-in-serotonin-transporter-knockout-rats-is-associated-with-increased-5-hydroxymethylcytosine-in-the-amygdala
#17
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
https://www.readbyqxmd.com/read/29423052/mage-a11-is-activated-through-tfcp2-zeb1-binding-sites-de-methylation-as-well-as-histone-modification-and-facilitates-escc-tumor-growth
#18
Shina Liu, Fei Liu, Weina Huang, Lina Gu, Lingjiao Meng, Yingchao Ju, Yunyan Wu, Juan Li, Lihua Liu, Meixiang Sang
Recently, we have reported that the product of Melanoma Antigens Genes (MAGE) family member MAGE-A11 is an independent poor prognostic marker for esophageal squamous cell carcinoma (ESCC). However, the reason how MAGE-A11 is activated in ESCC progression still remains unclear. In the current study, we demonstrated that DNA methylation and the subsequent histone posttranslational modifications play crucial roles in the regulation of MAGE-A11 in ESCC progression. We found that the methylation rate of TFCP2/ZEB1 binding site on MAGE-A11 promoter in ESCC tissues and cells is higher than the normal esophageal epithelial tissues and cells...
January 9, 2018: Oncotarget
https://www.readbyqxmd.com/read/29416619/the-inhibitory-activity-of-gallic-acid-against-dna-methylation-application-of-gallic-acid-on-epigenetic-therapy-of-human-cancers
#19
Yui-Ping Weng, Pin-Feng Hung, Wen-Yen Ku, Chang-Yuan Chang, Bo-Han Wu, Ming-Han Wu, Jau-Ying Yao, Ji-Rui Yang, Chia-Huei Lee
Epigenome aberrations have been observed in tobacco-associated human malignancies. (-)-epigallocatechin-3-gallate (EGCG) has been proven to modulate gene expression by targeting DNA methyltransferases (DNMTs) through a proposed mechanism involving the gallate moiety of EGCG. We show that gallic acid (GA) changes the methylome of lung cancer and pre-malignant oral cell lines and markedly reduces both nuclear and cytoplasmic DNMT1 and DNMT3B within 1 week. GA exhibits stronger cytotoxicity against the lung cancer cell line H1299 than EGCG...
January 2, 2018: Oncotarget
https://www.readbyqxmd.com/read/29413895/epigenetic-alterations-contribute-to-promoter-activity-of-imprinting-gene-igf2
#20
Qi-Fan Zheng, Bin Xu, Hui-Min Wang, Li-Hong Ding, Jin-Yang Liu, Ling-Yu Zhu, Huan Qiu, Li Zhang, Guang-Yi Ni, Jing Ye, Shu-Bin Gao, Guang-Hui Jin
The expression of insulin-like growth factor 2 (IGF2), a classical imprinting gene, didn't completely correlate with its imprinting profiles in hepatocellular carcinoma (HCC). The mechanistic importance of promoter activity in regulation of IGF2 has not been fully clarified. Here we show that histone 3 lysine 4 trimethylation (H3K4me3) modified by menin-MLL complex of IGF2 promoter contributes to promoter activity of IGF2. The strong binding of menin and abundant H3K4me3 at the DNA demethylated P3/4 promoters were observed in Hep3B cells with the robust expression of IGF2...
January 31, 2018: Biochimica et Biophysica Acta
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