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Hye-Jin Park, Kang-Woo Lee, Eun S Park, Stephanie Oh, Run Yan, Jie Zhang, Thomas G Beach, Charles H Adler, Michael Voronkov, Steven P Braithwaite, Jeffry B Stock, M Maral Mouradian
OBJECTIVE: Protein phosphatase 2A (PP2A) is a heterotrimeric holoenzyme composed of a catalytic C subunit, a structural A subunit, and one of several regulatory B subunits that confer substrate specificity. The assembly and activity of PP2A are regulated by reversible methylation of the C subunit. α-Synuclein, which aggregates in Parkinson disease (PD) and dementia with Lewy bodies (DLB), is phosphorylated at Ser129, and PP2A containing a B55α subunit is a major phospho-Ser129 phosphatase...
October 2016: Annals of Clinical and Translational Neurology
Federica Parodi, Roberta Carosio, Marco Ragusa, Cinzia Di Pietro, Marco Maugeri, Davide Barbagallo, Fabio Sallustio, Giorgio Allemanni, Maria Pia Pistillo, Ida Casciano, Alessandra Forlani, Francesco P Schena, Michele Purrello, Massimo Romani, Barbara Banelli
In neuroblastoma, the epigenetic landscape is more profoundly altered in aggressive compared to lower grade tumors and the concomitant hypermethylation of many genes, defined as "methylator phenotype", has been associated with poor outcome. DNA methylation can interfere with gene expression acting at distance through the methylation or demethylation of the regulatory regions of miRNAs. The multiplicity of miRNA targets may result in the simultaneous alteration of many biological pathways like cell proliferation, apoptosis, migration and differentiation...
October 14, 2016: Biochimica et Biophysica Acta
Yuli Hu, Shoujun Fan, Xiaobing Liao, Chao Chen, Liang Su, Xuegang Li
Berberine (BBR) is a bioactive plant ingredient derived from the roots and bark of Berberis aristata and Coptis chinensis and has a wide variety of pharmacological effects. 8-cetylberberine (8-BBR-C16) is the berberine (BBR) derivative reconstructed from adding octadecyl at C-8 of BBR to enhance its activity. This study presents a reliable method for the determination of BBR and 8-BBR-C16 in rat plasma, urine and feces. BBR and 8-BBR-C16 were determined by HPLC-UV after liquid-liquid extraction for plasma samples, and solid-phase extraction for urinary and fecal samples...
October 14, 2016: Journal of Pharmaceutical and Biomedical Analysis
Ornella Affinito, Giovanni Scala, Domenico Palumbo, Ermanno Florio, Antonella Monticelli, Gennaro Miele, Vittorio Enrico Avvedimento, Alessandro Usiello, Lorenzo Chiariotti, Sergio Cocozza
DNA methylation is often analyzed by reporting the average methylation degree of each cytosine. In this study, we used a single molecule methylation analysis in order to look at the methylation conformation of individual molecules. Using D-aspartate oxidase as a model gene, we performed an in-depth methylation analysis through the developmental stages of three different mouse tissues (brain, lung, and gut), where this gene undergoes opposite methylation destiny. This approach allowed us to track both methylation and demethylation processes at high resolution...
October 17, 2016: Epigenetics: Official Journal of the DNA Methylation Society
Fange Liu, Wesley Clark, Guanzheng Luo, Xiaoyun Wang, Ye Fu, Jiangbo Wei, Xiao Wang, Ziyang Hao, Qing Dai, Guanqun Zheng, Honghui Ma, Dali Han, Molly Evans, Arne Klungland, Tao Pan, Chuan He
tRNA is a central component of protein synthesis and the cell signaling network. One salient feature of tRNA is its heavily modified status, which can critically impact its function. Here, we show that mammalian ALKBH1 is a tRNA demethylase. It mediates the demethylation of N(1)-methyladenosine (m(1)A) in tRNAs. The ALKBH1-catalyzed demethylation of the target tRNAs results in attenuated translation initiation and decreased usage of tRNAs in protein synthesis. This process is dynamic and responds to glucose availability to affect translation...
October 8, 2016: Cell
Tyler A Johnson, Laura Milan-Lobo, Tao Che, Madeline Ferwerda, Eptisam Lambo, Nicole L McIntosh, Fei Li, Li He, Nicholas Lorig-Roach, Phillip Crews, Jennifer Lynne Whistler
Opioid therapeutics are excellent analgesics, whose utility is compromised by dependence. Morphine (1) and its clinically relevant derivatives such as OxyContin® (4), Vicodin® (5) and Dilaudid® (6) are "biased" agonists at the µ opioid receptor (OR), wherein they engage G-protein signaling but poorly engage β-arrestin and the endocytic machinery. In contrast, the endorphins, met-enkephalin (14) and β-endorphin (15), endogenous peptide agonists for ORs, are more potent analgesics then 1, show reduced liability for tolerance and dependence, and engage both G-protein and β-arrestin pathways as "balanced" agonists...
October 17, 2016: ACS Chemical Neuroscience
Rohit Mathur, Lalit Sehgal, Ondrej Havranek, Stefan Köhrer, Tamer Khashab, Neeraj Jain, Jan A Burger, Sattva S Neelapu, R Eric Davis, Felipe Samaniego
Histone methylation and demethylation regulates B-cell development, and their deregulation correlates with tumor chemoresistance in diffuse large B-cell lymphoma, limiting curative rates. Since histone methylation status correlates with disease aggressiveness and relapse, we investigated the therapeutic potential of inhibiting histone 3 Lys27 demethylase KDM6B, in-vitro, using the small molecule inhibitor GSK-J4. KDM6B is overexpressed in the DLBCL germinal center B-cell subtype, and higher KDM6B levels are associated with worse survival in DLBCL patients treated with R-CHOP...
October 14, 2016: Haematologica
Chike Bellarmine Item, Sharmane Escueta, Andrea Schanzer, Somayeh Farhadi, Thomas Metz, Maximilian Zeyda, Dorothea Möslinger, Susanne Greber-Platzer, Vassiliki Konstantopoulou
OBJECTIVES: Phenylketonuria (PKU) is characterized by a high phenylalanine (phe) in plasma and oxidative stress. However, the monitoring of oxidative stress in newborns with PKU using the activity levels of antioxidant enzymes is not optimal. We investigated the possibility of monitoring an increased reactive oxygen species (ROS) production using DNA methylation changes of an oxidative stress response element in the promoter region of an enzymatic antioxidant gene. DESIGN AND METHODS: Using DNA extracted from blood leukocytes, the cytosine phosphodiester bond guanine positions of an overlapping CCAAT box/metal response element (CGATTGGCTG) of the glutathione peroxidase 3 promoter activated by oxidative stimuli and expressed in plasma were analysed for methylation changes in 20 newborns with hyperphenylalaninemia and 20 healthy controls...
October 12, 2016: Clinical Biochemistry
Daisuke Mayumi, Hanako Mochimaru, Hideyuki Tamaki, Kyosuke Yamamoto, Hideyoshi Yoshioka, Yuichiro Suzuki, Yoichi Kamagata, Susumu Sakata
Coal-bed methane is one of the largest unconventional natural gas resources. Although microbial activity may greatly contribute to coal-bed methane formation, it is unclear whether the complex aromatic organic compounds present in coal can be used for methanogenesis. We show that deep subsurface-derived Methermicoccus methanogens can produce methane from more than 30 types of methoxylated aromatic compounds (MACs) as well as from coals containing MACs. In contrast to known methanogenesis pathways involving one- and two-carbon compounds, this "methoxydotrophic" mode of methanogenesis couples O-demethylation, CO2 reduction, and possibly acetyl-coenzyme A metabolism...
October 14, 2016: Science
Xin Li, Yun Liu, Tal Salz, Kasper D Hansen, Andrew P Feinberg
DNA methylation at the 5-postion of cytosine (5mC) is an epigenetic modification that regulates gene expression and cellular plasticity in development and disease. The ten-eleven translocation (TET) gene family oxidizes 5mC to 5-hydroxymethylcytosine (5hmC), providing an active mechanism for DNA demethylation, and may also provide its own regulatory function. Here we applied oxidative bisulfite sequencing to generate whole-genome DNA methylation and hydroxymethylation maps at single-base resolution in paired human liver and lung normal and cancer...
October 13, 2016: Genome Research
Nathalie Dehne, Bernhard Brüne
Hypoxia, by activating transcription factors induces transcription of some genes but it also reduces mRNA synthesis by mechanisms that are poorly defined. Activation of human macrophages with interleukin (IL)-4 showed that up-regulation of some IL-4 target genes was reduced when macrophages were incubated at 1% oxygen. Hypoxia impaired induction of chemokine (CC motif) ligand 18 (CCL18), although IL-4-induced DNA binding of the transcription factor STAT6 remained intact. In contrast, induction of serine peptidase inhibitor, Kunitz type (SPINT)2, another IL-4/STAT6 target gene, was not affected by hypoxia...
October 11, 2016: Biochimica et Biophysica Acta
Nicolás Herranz, Natàlia Dave, Alba Millanes-Romero, Laura Pascual, Lluis Morey, Víctor M Díaz, Víctor Lórenz-Fonfría, Ricardo Gutierrez-Gallego, Celia Jerónimo, Ane Iturbide, Luciano Di Croce, Antonio García de Herreros, Sandra Peiró
Methylation of histone H3 lysine 4 is linked to active transcription and can be removed by LSD1 or the JmjC domain-containing proteins by amino-oxidation or hydroxylation, respectively. Here we describe that its deamination can be catalyzed by lysyl oxidase-like 2 protein (LOXL2), presenting an unconventional chemical mechanism for H3K4 modification. Infrared spectroscopy and mass spectrometry analyses demonstrated that recombinant LOXL2 specifically deaminates trimethylated H3K4. Moreover, by regulating H3K4me3 deamination, LOXL2 activity is linked with the transcriptional control of the CDH1 gene...
October 13, 2016: FEBS Journal
Jianing Zhong, Xianfeng Li, Wanshi Cai, Yan Wang, Shanshan Dong, Jie Yang, Jian'an Zhang, Nana Wu, Yuanyuan Li, Fengbiao Mao, Cheng Zeng, Jinyu Wu, Xingzhi Xu, Zhong Sheng Sun
The Ten Eleven Translocation 1 (TET1) protein is a DNA demethylase that regulates gene expression through altering statue of DNA methylation. However, recent studies have demonstrated that TET1 could modulate transcriptional expression independent of its DNA demethylation activity; yet, the detailed mechanisms underlying TET1's role in such transcriptional regulation remain not well understood. Here, we uncovered that Tet1 formed a chromatin complex with histone acetyltransferase Mof and scaffold protein Sin3a in mouse embryonic stem cells by integrative genomic analysis using publicly available ChIP-seq data sets and a series of in vitro biochemical studies in human cell lines...
October 12, 2016: Nucleic Acids Research
Moshe Szyf
5'-hydroxymethylcytosine (5hmC) is a variant of the common covalent epigenetic modification of DNA 5'-methylcytosine (5mC). Although the presence of this modified base in mammalian DNA has been recognized for several decades, it has recently gained center stage as a suspected intermediate in enzymatic active demethylation of 5mC. The role of 5hmC remains elusive in spite of a large body of studies. It is proposed that 5hmC is a variant of the 5mC epigenetic signal and is involved in epigenetic regulation of gene function...
October 13, 2016: Epigenomics
Yoichi Munehira, Ze Yang, Or Gozani
Histone methylation dynamics play a critical role in cellular programming during development. For example, specific lysine methyltransferases (KMTs) and demethylases (KDMs) have been implicated in the differentiation of mesenchymal stem cells into various cell lineages. However, a systematic functional analysis for an entire family of KMT or KDM enzymes has not been performed. Here we test the function of all the known and candidate KDMs in myoblast and osteoblast differentiation using the C2C12 cell differentiation model system...
October 9, 2016: Journal of Molecular Biology
Maxime Janin, Manel Esteller
Mutations to the Krebs cycle enzyme fumarate hydratase in cancer cells leads to an accumulation of the oncometabolite fumarate. Sciacovelli et al. (2016) demonstrate an epigenetically dependent epithelial-to-mesenchymal transition mediated by modulation of the miR-200 cluster and TET demethylation in response to fumarate accumulation.
October 11, 2016: Cell Metabolism
Muthiah Suresh, Navin Kumar, Gorre Veeraraghavaiah, Sunit Hazra, Raj Bahadur Singh
The first synthesis of coprinol has been achieved from 2-methoxy-3,5-dimethylbenzaldehyde via the intermediacy of an indanone derivative where dialkylation, Friedel-Crafts acylation, demethylation, and regioselective formation of a primary -OH group from a chloroacetyl group are the key steps.
October 12, 2016: Journal of Natural Products
Jiaojiao Li, Shashank S Pawitwar, Barry P Rosen
Arsenic is the most pervasive environmental toxic substance. As a consequence of its ubiquity, nearly every organism has genes for resistance to inorganic arsenic. In bacteria these genes are found largely in bacterial arsenic resistance (ars) operons. Recently a parallel pathway for synthesis and degradation of methylated arsenicals has been identified. The arsM gene product encodes the ArsM (AS3MT in animals) As(iii) S-adenosylmethionine methyltransferase that methylates inorganic trivalent arsenite in three sequential steps to methylarsenite MAs(iii), dimethylarsenite (DMAs(iii) and trimethylarsenite (TMAs(iii))...
October 1, 2016: Metallomics: Integrated Biometal Science
Nidal E Muvarak, Khadiza Chowdhury, Limin Xia, Carine Robert, Eun Yong Choi, Yi Cai, Marina Bellani, Ying Zou, Zeba N Singh, Vu H Duong, Tyler Rutherford, Pratik Nagaria, Søren M Bentzen, Michael M Seidman, Maria R Baer, Rena G Lapidus, Stephen B Baylin, Feyruz V Rassool
Poly (ADP-ribose) polymerase inhibitors (PARPis) are clinically effective predominantly for BRCA-mutant tumors. We introduce a mechanism-based strategy to enhance PARPi efficacy based on DNA damage-related binding between DNA methyltransferases (DNMTs) and PARP1. In acute myeloid leukemia (AML) and breast cancer cells, DNMT inhibitors (DNMTis) alone covalently bind DNMTs into DNA and increase PARP1 tightly bound into chromatin. Low doses of DNMTis plus PARPis, versus each drug alone, increase PARPi efficacy, increasing amplitude and retention of PARP1 directly at laser-induced DNA damage sites...
October 10, 2016: Cancer Cell
Ferdinand von Meyenn, Rebecca V Berrens, Simon Andrews, Fátima Santos, Amanda J Collier, Felix Krueger, Rodrigo Osorno, Wendy Dean, Peter J Rugg-Gunn, Wolf Reik
Primordial germ cell (PGC) development is characterized by global epigenetic remodeling, which resets genomic potential and establishes an epigenetic ground state. Here we recapitulate PGC specification in vitro from naive embryonic stem cells and characterize the early events of epigenetic reprogramming during the formation of the human and mouse germline. Following rapid de novo DNA methylation during priming to epiblast-like cells, methylation is globally erased in PGC-like cells. Repressive chromatin marks (H3K9me2/3) and transposable elements are enriched at demethylation-resistant regions, while active chromatin marks (H3K4me3 or H3K27ac) are more prominent at regions that demethylate faster...
October 10, 2016: Developmental Cell
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