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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
Jennifer M SanMiguel, Lara K Abramowitz, Marisa S Bartolomei
Imprinted genes are expressed from one parental allele and regulated by differential DNA methylation at imprinting control regions (ICR). ICRs are reprogrammed in the germline through erasure and reestablishment of DNA methylation. Although much is known about DNA methylation establishment, DNA demethylation is less well understood. Recently, the Ten-Eleven Translocation proteins (TET1-3) have been shown to initiate DNA demethylation, with Tet1 -/- mice exhibiting aberrant levels of imprinted gene expression and ICR methylation...
March 12, 2018: Development
Sumiyo Morita, Takuro Horii, Izuho Hatada
DNA methylation, one of the most studied epigenetic modifications, regulates many biological processes. Dysregulation of DNA methylation is implicated in the etiology of several diseases, such as cancer and imprinting diseases. Accordingly, technologies designed to manipulate DNA methylation at specific loci are very important, and many epigenome editing technologies have been developed, based on zinc finger proteins, TALEs, and CRISPR/dCas9 targeting. We describe a protocol to induce and assess DNA demethylation on a target gene...
2018: Methods in Molecular Biology
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
Yansen Li, Zhanlong Shen, Hongpeng Jiang, Zhiyong Lai, Zhu Wang, Kewei Jiang, Yingjiang Ye, Shan Wang
Increasing evidence has shown that abnormal expression of miR-4284 participates in the progression of several types of cancer. However, the expression and the role of miR‑4284 in gastric cancer remain largely unknown. Therefore, in the present study the miR‑4284 expression levels in gastric cancer tissues and cell lines, was examined using reverse transcription‑quantitative polymerase chain reaction (RT‑qPCR) and found that miR‑4284 was significantly upregulated in 40 pairs of gastric cancer tissues and five gastric cancer cell lines compared to the corresponding normal tissues and GES‑1 cell line...
March 1, 2018: Molecular Medicine Reports
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
Jin Liu, Mingpeng Li, Xiancheng Liu, Fan Liu, Jianwei Zhu
Osteosarcoma has become one of the most common primary malignant tumors affecting children and adolescents. Although increasing evidence has indicated that microRNAs (miRNAs or miRs) play important roles in the development of osteosarcoma, the expression of miR‑27a‑3p and its effects on osteosarcoma are not yet fully understood. In the present study, our data demonstrated that the expression of miR‑27a‑3p in osteosarcoma cell lines was significantly higher than that in the normal human osteoblastic cell line, hFOB 1...
February 14, 2018: International Journal of Oncology
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
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
Xi Jiang, Chao Hu, Kyle Ferchen, Ji Nie, Xiaolong Cui, Chih-Hong Chen, Liting Cheng, Zhixiang Zuo, William Seibel, Chunjiang He, Yixuan Tang, Jennifer R Skibbe, Mark Wunderlich, William C Reinhold, Lei Dong, Chao Shen, Stephen Arnovitz, Bryan Ulrich, Jiuwei Lu, Hengyou Weng, Rui Su, Huilin Huang, Yungui Wang, Chenying Li, Xi Qin, James C Mulloy, Yi Zheng, Jiajie Diao, Jie Jin, Chong Li, Paul P Liu, Chuan He, Yuan Chen, Jianjun Chen
The original version of this Article contained an error in the spelling of the author James C. Mulloy, which was incorrectly given as James Mulloy. This has now been corrected in both the PDF and HTML versions of the Article.
February 9, 2018: Nature Communications
Min Ma, Qiong-Jie Zhou, Yu Xiong, Bin Li, Xiao-Tian Li
Previous studies have demonstrated a dynamic epigenetic regulation of genes expression in placenta trophoblasts and a dynamic imbalance of DNA methylation and hydroxymethylation. Reduced IGF-1 has been observed in preeclampsia. This study was to investigate the interactive roles between IGF-1 and the global DNA methylation/hydroxymethylation, and the status of DNA methylation/hydroxymethylation and associated enzymes such as DNMTs and TETs in peeeclamptic placentas and hypoxic trophoblasts. It was found that IGF-1 was decreased in preeclamptic placentas and hypoxic trophoblasts when compared to the control group using immunohistochemisty, western blot, qRT-PCR and ELISA...
2018: American Journal of Translational Research
Jinghan Wang, Fenglin Li, Zhixin Ma, Mengxia Yu, Qi Guo, Jiansong Huang, Wenjuan Yu, Yungui Wang, Jie Jin
Ten-Eleven-Translocation 1 (TET1) plays a role in the DNA methylation process and gene activation. Recent reports suggest TET1 acts as an oncogene in leukemia development. However, the clinical relevance and biological insight of TET1 expression in cytogenetically normal acute myeloid leukemia (CN-AML) is unknown. In this study, quantification of TET1 transcript by real-time quantitative PCR in bone marrow blasts was performed in 360 CN-AML patients. As a result, high TET1 expression was more common in M0/M1 morphology and genes of NPM1 mutations, and underrepresented in CEBPA double allele mutations in our AML patients...
January 31, 2018: EBioMedicine
Niki Karachaliou, Maria Gonzalez-Cao, Guillermo Crespo, Ana Drozdowskyj, Erika Aldeguer, Ana Gimenez-Capitan, Cristina Teixido, Miguel Angel Molina-Vila, Santiago Viteri, Maria De Los Llanos Gil, Salvador Martin Algarra, Elisabeth Perez-Ruiz, Ivan Marquez-Rodas, Delvys Rodriguez-Abreu, Remedios Blanco, Teresa Puertolas, Maria Angeles Royo, Rafael Rosell
Background: Programmed death-ligand 1 (PD-L1) may be induced by oncogenic signals or can be upregulated via interferon gamma (IFN-γ). We have explored whether the expression of IFNG, the gene encoding IFN-γ, is associated with clinical response to the immune checkpoint blockade in non-small cell lung cancer (NSCLC) and melanoma patients. The role of inflammation-associated transcription factors STAT3, IKBKE, STAT1 and other associated genes has also been examined. Methods: Total RNA from 17 NSCLC and 21 melanoma patients was analyzed by quantitative reverse transcription PCR...
2018: Therapeutic Advances in Medical Oncology
Ruiheng Yang, Hong Hong, Mengjun Wang, Zhongchao Ma
This study was aimed to figure out the association of single-nucleotide polymorphisms (SNPs) within miR-30a and its downstream molecules (i.e., Notch1, Snail1, p53, CD73, and TET1) with susceptibility to and prognosis of nephrotic syndrome (NS). In the aggregate, 265 patients and 281 healthy controls were gathered, and related laboratory indicators were examined. The miR-30a, Notch1, Snail1, TET1, p53, and CD73 expressions were also evaluated by quantitative real-time polymerase chain reaction (qRT-PCR), immunohistochemistry, or enzyme-linked immunosorbent assay...
January 22, 2018: DNA and Cell Biology
Jiyoung Lee, Ayumi Matsuzawa, Hirosuke Shiura, Akito Sutani, Fumitoshi Ishino
Epigenetic properties of cultured embryonic stem cells (ESCs), including DNA methylation imprinting, are important because they affect the developmental potential. Here, we tested a variety of culture media, including knockout serum replacement (KSR) and fetal bovine serum (FBS) with or without inhibitors of Gsk3β and Mek1/2 (2i) at various time points. In addition to the previously known passage-dependent global changes, unexpected dynamic DNA methylation changes occurred in both maternal and paternal differentially methylated regions: under the widely used condition of KSR with 2i, a highly hypomethylated state occurred at early passages (P1-7) as well as P10, but DNA methylation increased over further passages in most conditions, except under KSR with 2i at P25...
January 22, 2018: Genes to Cells: Devoted to Molecular & Cellular Mechanisms
Jessy Cartier, Chinthika Piyasena, Sarah A Sparrow, James P Boardman, Amanda J Drake
Preterm birth affects 5-18% of all babies and is associated with neurodevelopmental impairment and increased neuropsychiatric disease risk. Although preterm birth associates with differential DNA methylation at neurodevelopmental genes in buccal DNA, including Leucine-rich alpha-2-glycoprotein 1 (LRG1), it is not known whether these differences also occur in the brain, or if they persist. Thus, there is a need for animal models or in vitro systems in which to undertake longitudinal and mechanistic studies. We used a combination of in vivo rat studies and ex vivo experiments in rat cortical slices to explore their utility in modelling the human preterm brain...
January 22, 2018: European Journal of Neuroscience
William M Skiles, Avery Kester, Jane H Pryor, Mark E Westhusin, Michael C Golding, Charles R Long
Embryo culture and assisted reproductive technologies have been associated with a disproportionately high number of epigenetic abnormalities in the resulting offspring. However, the mechanisms by which these techniques influence the epigenome remain poorly defined. In this study, we evaluated the capacity of oxygen concentration to influence the transcriptional control of a selection of key enzymes regulating chromatin structure. In mouse embryonic stem cells, oxygen concentrations modulated the transcriptional regulation of the TET family of enzymes, as well as the de novo methyltransferase Dnmt3a...
January 12, 2018: Gene Expression Patterns: GEP
Kuo-Chiang Wang, Chi-Hsiang Kang, Chung-Yu Tsai, Nan-Hua Chou, Ya-Ting Tu, Guan-Cheng Li, Hing-Chung Lam, Shiuh-Inn Liu, Po-Min Chang, Yan-Hwai Lin, Kuo-Wang Tsai
A sixth base, 5-hydroxymethylcytosine (5hmC), is formed by the oxidation of 5-methylcytosine (5mC) via the catalysis of the ten-eleven translocation (TET) protein family in cells. Expression levels of 5hmC are frequently depleted during carcinogenesis. However, the detailed mechanisms underlying the depletion of 5hmC expression in gastric cancer cells remains unclear, and further research is required. The present study examined the expression levels of 5mC and 5hmC and the expression levels of TET1 and TET2 in gastric cancer tissues using immunohistochemistry...
January 2018: Oncology Letters
Qimeng Li, Baicheng Yi, Zhihui Feng, Runsha Meng, Cheng Tian, Qiong Xu
OBJECTIVES: Ten-eleven translocation 1 (TET1) is a DNA methylcytosine (mC) dioxygenase discovered recently that can convert 5-mC into 5-hydroxymethylcytosine (5hmC). We previously reported that TET1 promotes odontoblastic differentiation of human dental pulp cells (hDPCs). The gene encoding the family with sequence similarity 20, member C (FAM20C) protein, is a potential TET1 target and showed demethylation during odontoblastic differentiation of hDPCs in our previous study. This study aimed to explore whether TET1-mediated hydroxymethylation could activate the FAM20C gene, thereby regulating hDPC differentiation...
December 25, 2017: Cell Proliferation
Xi Jiang, Chao Hu, Kyle Ferchen, Ji Nie, Xiaolong Cui, Chih-Hong Chen, Liting Cheng, Zhixiang Zuo, William Seibel, Chunjiang He, Yixuan Tang, Jennifer R Skibbe, Mark Wunderlich, William C Reinhold, Lei Dong, Chao Shen, Stephen Arnovitz, Bryan Ulrich, Jiuwei Lu, Hengyou Weng, Rui Su, Huilin Huang, Yungui Wang, Chenying Li, Xi Qin, James C Mulloy, Yi Zheng, Jiajie Diao, Jie Jin, Chong Li, Paul P Liu, Chuan He, Yuan Chen, Jianjun Chen
Effective therapy of acute myeloid leukemia (AML) remains an unmet need. DNA methylcytosine dioxygenase Ten-eleven translocation 1 (TET1) is a critical oncoprotein in AML. Through a series of data analysis and drug screening, we identified two compounds (i.e., NSC-311068 and NSC-370284) that selectively suppress TET1 transcription and 5-hydroxymethylcytosine (5hmC) modification, and effectively inhibit cell viability in AML with high expression of TET1 (i.e., TET1-high AML), including AML carrying t(11q23)/MLL-rearrangements and t(8;21) AML...
December 13, 2017: Nature Communications
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