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DNA demethylation

Xue-Dong Liu, Xiao Liu, Xiu-Fen Guo, Jian-Min Luo, Ying-Hua Li
OBJECTIVE: To investigate the relationship of DNA methyltransferase 1 ( DNMT1 ) with hematopoietic cell phosphatase (SHP-1) gene expression and promoter 2 methylation status in cell line K562. METHODS: The promoter sequence of SHP-1 gene promoter 2 in NCBI database was analyzed, the K562 cells were transfected with the lentiviral plasmids-the specified retroviral vector psiHIV-mU6-shDNMT1 and psiHIV-mU6-mcherryFP-control. The methylation status of SHP-1 gene promoter 2 in K562 cells was detected by methylation-specific polymerase chain reaction (MSP) and bisulfite-modified sequencing (BSP)...
April 2018: Zhongguo Shi Yan Xue Ye Xue za Zhi
Kosuke Nishio, Roman Belle, Takayuki Katoh, Akane Kawamura, Toru Sengoku, Kazuharu Hanada, Noboru Ohsawa, Mikako Shirouzu, Shigeyuki Yokoyama, Hiroaki Suga
The ten-eleven translocation (TET) protein family, consisting of three isoforms (TET1/2/3), have been found in mammalian cells and have a crucial role in 5-methycytosine demethylation in genomic DNA through the catalysis of oxidation reactions assisted by 2-oxoglutarate (2OG). DNA methylation/demethylation contributes to the regulation of gene expression at the transcriptional level, and recent studies have revealed that TET1 is highly elevated in malignant cells of various diseases and related to malignant alteration...
April 17, 2018: Chembiochem: a European Journal of Chemical Biology
Adam T McLain, Christopher Faulk
Gene promoters are evolutionarily conserved across holozoans and enriched in CpG sites, the target for DNA methylation. As animals age, the epigenetic pattern of DNA methylation degrades, with highly methylated CpG sites gradually becoming demethylated while CpG islands increase in methylation. Across vertebrates, aging is a trait that varies among species. We used this variation to determine whether promoter CpG density correlates with species' maximum lifespan. Human promoter sequences were used to identify conserved regions in 131 mammals and a subset of 28 primate genomes...
April 14, 2018: Aging
Christopher T Coey, Alexander C Drohat
Thymine DNA glycosylase (TDG) excises thymine from mutagenic G·T mispairs generated by deamination of 5-methylcytosine (mC) and it removes two mC derivatives, 5-formylcytosine (fC) and 5-carboxylcytosine (caC), in a multistep pathway for DNA demethylation. TDG is modified by small ubiquitin-like modifier (SUMO) proteins, but the impact of sumoylation on TDG activity is poorly defined and the functions of TDG sumoylation remain unclear. We determined the effect of TDG sumoylation, by SUMO-1 or SUMO-2, on substrate binding and catalytic parameters...
April 12, 2018: Nucleic Acids Research
Rui Fu, Yan Ding, Jie Luo, Kuan Ming Huang, Xiang Jun Tang, Dong Sheng Li, Shi Wen Guo
Ten-eleven translocation 1 catalyzes the conversion of 5-methylcytosine (5mC) to 5-hydroxymethylcytosine (5hmC), which plays an important role in epigenetics and is related to the malignant biological behavior of tumors. However, its regulatory role in glioma remains unclear. In this study, the levels of 5mC and 5hmC were detected using immunohistochemistry, dot-blot, hMeDIP-chip, and western blot in glioma tissues and normal brain tissues, whereas 5hmC differentially enriched genes were determined and further validated...
April 13, 2018: Neuroreport
Yami Liu, Wen Peng, Kai Qu, Xiaolong Lin, Zhaolin Zeng, Jiaojiao Chen, Dangheng Wei, Zuo Wang
Atherosclerosis is the underlying cause of cardio-cerebrovascular disease. However, the mechanisms of atherosclerosis are still unclear. The modification of DNA methylation has an important role in atherosclerosis development. As a member of the Ten-eleven translocation (TET) family, TET methylcytosine dioxygenase 2 (TET2) can modify DNA methylation by catalyzing 5-methylcytosine to 5-hydroxymethylcytosine and mediate DNA demethylation. Recent findings suggest that TET2 is related to the phenotype transformation of vascular smooth muscle cells, endothelial dysfunction, and inflammation of macrophage, the key factors of atherosclerosis...
April 13, 2018: DNA and Cell Biology
Ana Xavier-Magalhães, Céline S Gonçalves, Anne Fogli, Tatiana Lourenço, Marta Pojo, Bruno Pereira, Miguel Rocha, Maria Celeste Lopes, Inês Crespo, Olinda Rebelo, Herminio Tão, João Lima, Ricardo Moreira, Afonso A Pinto, Chris Jones, Rui M Reis, Joseph F Costello, Philippe Arnaud, Nuno Sousa, Bruno M Costa
The lncRNA HOTAIR has been implicated in several human cancers. Here, we evaluated the molecular alterations and upstream regulatory mechanisms of HOTAIR in glioma, the most common primary brain tumors, and its clinical relevance. HOTAIR gene expression, methylation, copy-number and prognostic value were investigated in human gliomas integrating data from online datasets and our cohorts. High levels of HOTAIR were associated with higher grades of glioma, particularly IDH wild-type cases. Mechanistically, HOTAIR was overexpressed in a gene dosage-independent manner, while DNA methylation levels of particular CpGs in HOTAIR locus were associated with HOTAIR expression levels in GBM clinical specimens and cell lines...
March 20, 2018: Oncotarget
Usha Panchapakesan, Carol Pollock
Drug repurposing, is the re-tasking of known medications for new clinical indications. Advantages, compared to de novo drug development, include reduced cost and time to market plus the added benefit of a known pharmacokinetic and safety profiles. Suitable drug candidates are identified through serendipitous observations, data mining, or increased understanding of disease mechanisms. This review highlights drugs suited for repurposing in kidney disease. The main cause of mortality in patients with chronic kidney disease is cardiovascular disease...
April 6, 2018: Kidney International
Tong Jin, Jianyu Hao, Daiming Fan
Tobacco smoking is an independent risk factor for the initiation of pancreatic cancer (PC). Hypermethylation of tumor suppressor genes has been demonstrated to be associated with smoking. This study aimed to find the relationship between nicotine exposure and hypermethylation of tumor suppressor genes in normal pancreatic epithelial cells. Human pancreatic epithelial cells ware cultured exposing to nicotine and the methylation status of tumor suppressor genes were detected. Proenkephalin (PENK) was chosen as the target gene and methylation level of PENK promoter region was measured...
April 4, 2018: Biochemical and Biophysical Research Communications
Fan Wu, Jintao Wang, Jianming Sun, Liman Shen, Meijuan Liu, Erjun Zhao
The present study aimed to investigate whether procaine may upregulate the expression of aquaporin‑5 (AQP5) in human salivary gland ductal cells and the underlying mechanisms of this upregulation. Immortalized normal human salivary gland ductal cells (NS‑SV‑DC), lacking AQP5 protein expression, were used to measure the glandular secretion rate following treatment with procaine, and the protein expression levels of AQP5 in NS‑SV‑DC cells were measured by western blotting. In order to investigate the mechanism of procaine action on AQP5 protein expression, the protein expression and activity of DNA methyltransferase (DNMT)1, and the CpG methylation of AQP5, were investigated further...
March 29, 2018: Molecular Medicine Reports
Toru Tanaka, Kohei Izawa, Yusuke Maniwa, Maki Okamura, Atsumasa Okada, Tomoko Yamaguchi, Keisuke Shirakura, Naoki Maekawa, Hayato Matsui, Kenji Ishimoto, Nobumasa Hino, Osamu Nakagawa, William C Aird, Hiroyuki Mizuguchi, Kenji Kawabata, Takefumi Doi, Yoshiaki Okada
Although transcription factors regulating endothelial cell (EC)-specific gene expression have been identified, it is not known how those factors induce EC-specificity. We previously reported that DNA hypomethylation of the proximal promoter elicits EC-specific expression of Roundabout4 (Robo4). However, the mechanisms establishing EC-specific hypomethylation of the Robo4 promoter remain unknown. In this study, we demonstrated that the hypermethylated Robo4 proximal promoter is demethylated as human iPS cells differentiate into endothelial cells...
April 4, 2018: Scientific Reports
Valeriya Gaysinskaya, Brendan F Miller, Chiara De Luca, Godfried W van der Heijden, Kasper D Hansen, Alex Bortvin
BACKGROUND: Meiosis is a specialized germ cell cycle that generates haploid gametes. In the initial stage of meiosis, meiotic prophase I (MPI), homologous chromosomes pair and recombine. Extensive changes in chromatin in MPI raise an important question concerning the contribution of epigenetic mechanisms such as DNA methylation to meiosis. Interestingly, previous studies concluded that in male mice, genome-wide DNA methylation patters are set in place prior to meiosis and remain constant subsequently...
April 4, 2018: Epigenetics & Chromatin
Lisa Boureau, Andrea Constantinof, Vasilis G Moisiadis, Stephen G Matthews, Moshe Szyf
AIM: To determine the state of methylation of DNA molecules in the guinea pig hippocampus that are associated with either poised or active enhancers. METHODS: We used sequential chromatin immunoprecipitation-bisulfite-sequencing with an antibody to H3K4me1 to map the state of methylation of DNA that is found within enhancers. Actively transcribing transcription start sites were mapped by chromatin immunoprecipitation-sequencing with an antibody to RNApolII-PS5. Total DNA methylation was mapped using reduced representation bisulfite sequencing...
April 4, 2018: Epigenomics
Sucharitha Iyer, Sunita K Agarwal
Epigenetic regulation is emerging as a key feature in the molecular characteristics of various human diseases. Epigenetic aberrations can occur from mutations in genes associated with epigenetic regulation, improper deposition, removal or reading of histone modifications, DNA methylation/demethylation, and impaired non-coding RNA interactions in chromatin. Menin, the protein product of the gene causative for the multiple endocrine neoplasia type 1 (MEN1) syndrome, interacts with chromatin-associated protein complexes and also regulates some non-coding RNAs, thus participating in epigenetic control mechanisms...
April 3, 2018: Journal of Molecular Endocrinology
Filipe Mega, André Luís Ferreira de Meireles, Francele Valente Piazza, Christiano Spindler, Ethiane Segabinazi, Gabriela Dos Santos Salvalaggio, Matilde Achaval, Simone Marcuzzo
Maternal exercise is known to have beneficial effects in progeny development, but the influence of paternal exercise on the offspring still unclear. Since spermatogenesis is a continuous process, the father's life experiences can reprogram epigenetic content of the sperm and somehow interfere on offspring phenotype. This study was designed to evaluate the effects of paternal physical exercise on cognitive and physical development and on hippocampal DNA methylation levels of the offspring. Adult male Wistar rats were divided into two groups: sedentary and exercised...
March 31, 2018: Behavioural Brain Research
Line Heylen, Bernard Thienpont, Maarten Naesens, Pieter Busschaert, Jeroen Depreeuw, Dominiek Smeets, Ina Jochmans, Diethard Monbaliu, Jacques Pirenne, Evelyne Lerut, Bart Ghesquiere, Dirk Kuypers, Diether Lambrechts, Ben Sprangers
Background Ischemia during kidney transplant causes chronic allograft injury and adversely affects outcome, but the underlying mechanisms are incompletely understood. In tumors, oxygen shortage reduces the DNA demethylating activity of the ten-11 translocation (TET) enzymes, yielding hypermethylated genomes that promote tumor progression. We investigated whether ischemia similarly induces DNA hypermethylation in kidney transplants and contributes to chronic injury. Methods We profiled genome-wide DNA methylation in three cohorts of brain-dead donor kidney allograft biopsy specimens: a longitudinal cohort with paired biopsy specimens obtained at allograft procurement (preischemia; n =13), after implantation and reperfusion (postischemia; n =13), and at 3 or 12 months after transplant ( n =5 each); a cross-sectional cohort with preimplantation biopsy specimens ( n =82); and a cross-sectional cohort with postreperfusion biopsy specimens ( n =46)...
April 2, 2018: Journal of the American Society of Nephrology: JASN
Yuqing Yang, Irene Yang, Mingnan Cao, Zheng-Yuan Su, Renyi Wu, Yue Guo, Mingzhu Fang, Ah-Ng Kong
Nuclear factor erythroid-2-related factor-2 (Nrf2 or NFE2L2) is a master regulator of the anti-oxidative stress response, which is involved in the defense against many oxidative stress/inflammation-mediated diseases, including anticancer effects elicited by an increasing number of natural products. Our previous studies showed that the epigenetic modification of the Nrf2 gene plays a key role in restoring the expression of Nrf2. In this study, we aimed to investigate the epigenetic regulation of Nrf2 by astaxanthin (AST) and fucoxanthin (FX), carotenoids which are abundant in microalgae and seaweeds, in mouse skin epidermal JB6 P+ cells...
February 20, 2018: AAPS Journal
Karla M O'Neill, Rachelle E Irwin, Sarah-Jayne Mackin, Sara-Jayne Thursby, Avinash Thakur, Ciske Bertens, Laura Masala, Jayne E P Loughery, Darragh G McArt, Colum P Walsh
BACKGROUND: DNA methylation plays a vital role in the cell, but loss-of-function mutations of the maintenance methyltransferase DNMT1 in normal human cells are lethal, precluding target identification, and existing hypomorphic lines are tumour cells. We generated instead a hypomorphic series in normal hTERT-immortalised fibroblasts using stably integrated short hairpin RNA. RESULTS: Approximately two-thirds of sites showed demethylation as expected, with one-third showing hypermethylation, and targets were shared between the three independently derived lines...
March 29, 2018: Epigenetics & Chromatin
Yongjie Feng, Lin Wang, Mingyong Wang
Lung cancer is the most common cause of cancer-related death. Non-small cell lung cancer (NSCLC) accounts for 80-85% of total lung cancer cases. Dachshund homolog 1, or DACH1, is a protein encoded by the DACH1 gene in humans. DACH1 inhibits lung adenocarcinoma invasion and tumor growth, but has a lower expression in NSCLC. To investigate the mechanisms of decreased DACH1 expression, its DNA methylation patterns were investigated. The results showed a higher methylation rate in NSCLC compared to in adjacent normal lung tissues...
March 28, 2018: Biochemistry and Cell Biology, Biochimie et Biologie Cellulaire
Enguerran Mouly, Hussein Ghamlouch, Veronique Della-Valle, Laurianne Scourzic, Cyril Quivoron, Damien Roos-Weil, Patrycja Pawlikowska, Véronique Saada, M'Boyba K Diop, Cécile K Lopez, Michaela Fontenay, Philippe Dessen, Ivo P Touw, Thomas Mercher, Said Aoufouchi, Olivier A Bernard
The TET2 gene encodes an α-ketoglutarate-dependent dioxygenase able to oxidize 5-methylcytosine into 5-hydroxymethylcytosine, which is a step toward active DNA demethylation. TET2 is frequently mutated in myeloid malignancies but also in B- and T-cell malignancies. TET2 somatic mutations are also identified in healthy elderly individuals with clonal hematopoiesis. Tet2 -deficient mouse models showed widespread hematological differentiation abnormalities, including myeloid, T-cell, and B-cell malignancies. We show here that, similar to what is observed with constitutive Tet2 -deficient mice, B-cell-specific Tet2 knockout leads to abnormalities in the B1-cell subset and a development of B-cell malignancies after long latency...
March 27, 2018: Blood Advances
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