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Can Cai, Huihong Yu, Guangming Huang, Xuan Du, Xiaoqing Yu, Youping Zhou, Wei Shen
Non‑alcoholic fatty liver disease (NAFLD) is a manifestation of metabolic syndrome in the liver and is closely associated with diabetes; however, its pathogenesis remains to be elucidated. Carbohydrate responsive element binding protein (ChREBP), the hub of glucolipid metabolism, regulates the induction of fatty acid synthase (FASN), the key enzyme of de novo lipogenesis, by directly binding to carbohydrate response element (ChoRE) in its promoter. Investigations of histone modifications on NAFLD remain in their infancy...
May 22, 2018: International Journal of Molecular Medicine
Lu Wang, Zibo Zhao, Patrick A Ozark, Damiano Fantini, Stacy A Marshall, Emily J Rendleman, Kira A Cozzolino, Nundia Louis, Xingyao He, Marc A Morgan, Yoh-Hei Takahashi, Clayton K Collings, Edwin R Smith, Panagiotis Ntziachristos, Jeffrey N Savas, Lihua Zou, Rintaro Hashizume, Joshua J Meeks, Ali Shilatifard
The lysine methyltransferase KMT2C (also known as MLL3), a subunit of the COMPASS complex, implements monomethylation of Lys4 on histone H3 (H3K4) at gene enhancers. KMT2C (hereafter referred to as MLL3) frequently incurs point mutations across a range of human tumor types, but precisely how these lesions alter MLL3 function and contribute to oncogenesis is unclear. Here we report a cancer mutational hotspot in MLL3 within the region encoding its plant homeodomain (PHD) repeats and demonstrate that this domain mediates association of MLL3 with the histone H2A deubiquitinase and tumor suppressor BAP1...
May 21, 2018: Nature Medicine
David Roquis, Aaron Taudt, Kathrin K Geyer, Gilda Padalino, Karl F Hoffmann, Nancy Holroyd, Matt Berriman, Benoît Aliaga, Cristian Chaparro, Christoph Grunau, Ronaldo de Carvalho Augusto
Epigenetic mechanisms and chromatin structure play an important role in development. Their impact is therefore expected to be strong in parasites with complex life cycles and multiple, strikingly different, developmental stages, i.e. developmental plasticity. Some studies have already described how the chromatin structure, through histone modifications, varies from a developmental stage to another in a few unicellular parasites. However, this, to our knowledge, has never been done before in multicellular metazoan parasites...
May 21, 2018: PLoS Pathogens
Bhaskar Bhushan, Alexandre Erdmann, Yijia Zhang, Roman Belle, Catrine Johannson, Udo Oppermann, Richard J Hopkinson, Christopher J Schofield, Akane Kawamura
Plant homeodomain (PHD) containing proteins are important epigenetic regulators and are of interest as potential drug targets. Inspired by the amiodarone derivatives reported to inhibit the PHD finger 3 of KDM5A (KDM5A(PHD3)), a set of compounds were synthesised. Amiodarone and its derivatives were observed to weakly disrupt the interactions of a histone H3K4me3 peptide with KDM5A(PHD3). Selected amiodarone derivatives inhibited catalysis of KDM5A, but in a PHD-finger independent manner. Amiodarone derivatives also bind to H3K4me3-binding PHD-fingers from the KDM7 subfamily...
March 19, 2018: Bioorganic & Medicinal Chemistry
Ayami Sato, Haruka Ueno, Momoka Fusegi, Saki Kaneko, Kakeru Kohno, Nantiga Virgona, Akira Ando, Yuko Sekine, Tomohiro Yano
BACKGROUND: Wnt signaling plays an essential role in tumor cell growth, including the development of malignant mesothelioma (MM). Epigenetic silencing of negative Wnt regulators leading to constitutive Wnt signaling has been observed in various cancers and warrants further attention. We have reported that a succinate ether derivative of α-tocotrienol (T3E) has potent cytotoxic effects in MM cells. Thus, in this study, we investigated whether the anti-MM effect of T3E could be mediated via the epigenetic alteration of the Wnt antagonist gene, Dickkopf-1 (DKK1)...
May 15, 2018: Pharmacology
Xiangjiu Kong, Anne D van Diepeningen, Theo A J van der Lee, Cees Waalwijk, Jingsheng Xu, Jin Xu, Hao Zhang, Wanquan Chen, Jie Feng
Post-translational modifications of chromatin structure by histone acetyltransferase (HATs) play a central role in the regulation of gene expression and various biological processes in eukaryotes. Although HAT genes have been studied in many fungi, few of them have been functionally characterized. In this study, we identified and characterized four putative HATs ( FgGCN5, FgRTT109, FgSAS2, FgSAS3 ) in the plant pathogenic ascomycete Fusarium graminearum , the causal agent of Fusarium head blight of wheat and barley...
2018: Frontiers in Microbiology
Kinisha Gala, Qing Li, Amit Sinha, Pedram Razavi, Madeline Dorso, Francisco Sanchez-Vega, Young Rock Chung, Ronald Hendrickson, James Hsieh, Michael Berger, Nikolaus Schultz, Alessandro Pastore, Omar Abdel-Wahab, Sarat Chandarlapaty
Estrogen receptor alpha (ERα) is a ligand-activated nuclear receptor that directs proliferation and differentiation in selected cancer cell types including mammary-derived carcinomas. These master-regulatory functions of ERα require trans-acting elements such as the pioneer factor FOXA1 to establish a genomic landscape conducive to ERα control. Here, we identify the H3K4 methyltransferase KMT2C as necessary for hormone-driven ERα activity and breast cancer proliferation. KMT2C knockdown suppresses estrogen-dependent gene expression and causes H3K4me1 and H3K27ac loss selectively at ERα enhancers...
May 14, 2018: Oncogene
Jian Xu, Benjamin L Kidder
Trophoblast stem (TS) cells derived from the trophectoderm (TE) of mammalian embryos have the ability to self-renew indefinitely or differentiate into fetal lineages of the placenta. Epigenetic control of gene expression plays an instrumental role in dictating the fate of TS cell self-renewal and differentiation. However, the roles of histone demethylases and activating histone modifications such as methylation of histone 3 lysine 4 (H3K4me3/me2) in regulating TS cell expression programs, and in priming the epigenetic landscape for trophoblast differentiation, are largely unknown...
May 10, 2018: Biology Open
Simin Li, Luyan Shen, Ke-Neng Chen
BACKGROUND: Histone H3 lysine 4 methylation (H3K4 methylation), including mono-methylation (H3K4me1), di-methylation (H3K4me2), or tri-methylation (H3K4me3), is one of the epigenetic modifications to histone proteins, which are related to the transcriptional activation of genes. H3K4 methylation has both tumor inhibiting and promoting effects, and the prognostic value of H3K4 methylation in cancer remains controversial. Therefore, we performed a systematic review and meta-analysis to examine the association between H3K4 methylation and cancer prognosis...
May 8, 2018: Thoracic Cancer
Jing-Yang He, Qiu-Ying Liu, Ling Wei, Zhong-Jian Liu, Yuan Huang, Xiao-Qin Yu, Bo Li, Yang Qin
OBJECTIVE: To study the regulation of suppressor of cytokine signaling 3 (SOCS3) expression bythe brother of the regulator of the imprinted site (BORIS) in hepatocellular carcinoma cell. METHODS: The expression of SOCS3 mRNA in HCC cell lines was detected by real-time quantitative PCR (qRT-PCR). The expression of SOCS3 protein in knockdown and overexpression BORIS of HCC cell lines was tested by Western blot. The SOCS3 gene promoter methylation statusin the knockdown and overexpression BORIS of hepatocarcinoma cell lines was detected by using methylation specific PCR (MSP-PCR) method...
January 2018: Sichuan da Xue Xue Bao. Yi Xue Ban, Journal of Sichuan University. Medical Science Edition
Ryo Tamura, Shigehiro Doi, Ayumu Nakashima, Kensuke Sasaki, Kazuya Maeda, Toshinori Ueno, Takao Masaki
Transforming growth factor-β1 (TGF-β1) is a major mediator of peritoneal fibrosis and reportedly affects expression of the H3K4 methyltransferase, SET7/9. SET7/9-induced H3K4 mono-methylation (H3K4me1) critically activates transcription of fibrosis-related genes. In this study, we examined the effect of SET7/9 inhibition on peritoneal fibrosis in mice and in human peritoneal mesothelial cells (HPMCs). We also examined SET7/9 expression in nonadherent cells isolated from the effluent of peritoneal dialysis (PD) patients...
2018: PloS One
Dhaval Varshney, Olivia Lombardi, Gabriele Schweikert, Sianadh Dunn, Olga Suska, Victoria H Cowling
mRNA cap addition occurs early during RNA Pol II-dependent transcription, facilitating pre-mRNA processing and translation. We report that the mammalian mRNA cap methyltransferase, RNMT-RAM, promotes RNA Pol II transcription independent of mRNA capping and translation. In cells, sublethal suppression of RNMT-RAM reduces RNA Pol II occupancy, net mRNA synthesis, and pre-mRNA levels. Conversely, expression of RNMT-RAM increases transcription independent of cap methyltransferase activity. In isolated nuclei, recombinant RNMT-RAM stimulates transcriptional output; this requires the RAM RNA binding domain...
May 1, 2018: Cell Reports
Kuo-Hsuan Hung, Yong H Woo, I-Ying Lin, Chin-Hsiu Liu, Li-Chieh Wang, Hsin-Yu Chen, Bor-Luen Chiang, Kuo-I Lin
T follicular helper (Tfh) cell-derived signals promote activation and proliferation of antigen-primed B cells. It remains unclear whether epigenetic regulation is involved in the B cell responses to Tfh cell-derived signals. Here, we demonstrate that Tfh cell-mimicking signals induce the expression of histone demethylases KDM4A and KDM4C, and the concomitant global down-regulation of their substrates, H3K9me3/me2, in B cells. Depletion of KDM4A and KDM4C potentiates B cell activation and proliferation in response to Tfh cell-derived signals...
April 30, 2018: Nucleic Acids Research
Natasha C Chang, Marie-Claude Sincennes, Fabien P Chevalier, Caroline E Brun, Melanie Lacaria, Jessica Segalés, Pura Muñoz-Cánoves, Hong Ming, Michael A Rudnicki
Asymmetrically dividing muscle stem cells in skeletal muscle give rise to committed cells, where the myogenic determination factor Myf5 is transcriptionally activated by Pax7. This activation is dependent on Carm1, which methylates Pax7 on multiple arginine residues, to recruit the ASH2L:MLL1/2:WDR5:RBBP5 histone methyltransferase complex to the proximal promoter of Myf5. Here, we found that Carm1 is a specific substrate of p38γ/MAPK12 and that phosphorylation of Carm1 prevents its nuclear translocation...
April 19, 2018: Cell Stem Cell
Devendran A Sadasivam, Der-Hwa Huang
Polycomb group (PcG) repressors confer epigenetically heritable silencing on key regulatory genes through histone H3 trimethylation on lysine 27 (H3K27me3). How the silencing state withstands antagonistic activities from co-expressed trithorax group (trxG) activators is unclear. Using overexpression of Trx H3K4 methylase to perturb the silenced state, we find a dynamic process triggered in a stepwise fashion to neutralize the inductive impacts from excess Trx. Shortly after Trx overexpression, there are global increases in H3K4 trimethylation and RNA polymerase II phosphorylation, marking active transcription...
April 16, 2018: Journal of Cell Science
Zhe Nie, Lihong Shi, Chon Lai, Shawn M O'Connell, Jiangchun Xu, Ryan K Stansfield, David J Hosfield, James M Veal, Jeffrey A Stafford
Histone lysine demethylases (KDMs) play a key role in epigenetic regulation and KDM5A and KDM5B have been identified as potential anti-cancer drug targets. Using structural information from known KDM4 and KDM5 inhibitors, a potent series of pyrazolylpyridines was designed. Structure-activity relationship (SAR) exploration resulted in the identification of compound 33, an orally available, potent inhibitor of KDM5A/5B with promising selectivity. Potent cellular inhibition as measured by levels of tri-methylated H3K4 was demonstrated with compound 33 in the breast cancer cell line ZR-75-1...
May 15, 2018: Bioorganic & Medicinal Chemistry Letters
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
Samuel K McBrayer, Benjamin A Olenchock, Gabriel J DiNatale, Diana D Shi, Januka Khanal, Rebecca B Jennings, Jesse S Novak, Matthew G Oser, Alissa K Robbins, Rebecca Modiste, Dennis Bonal, Javid Moslehi, Roderick T Bronson, Donna Neuberg, Quang-De Nguyen, Sabina Signoretti, Julie-Aurore Losman, William G Kaelin
Inactivation of the retinoblastoma gene ( RB1 ) product, pRB, is common in many human cancers. Targeting downstream effectors of pRB that are central to tumorigenesis is a promising strategy to block the growth of tumors harboring loss-of-function RB1 mutations. One such effector is retinoblastoma-binding protein 2 (RBP2, also called JARID1A or KDM5A), which encodes an H3K4 demethylase. Binding of pRB to RBP2 has been linked to the ability of pRB to promote senescence and differentiation. Importantly, genetic ablation of RBP2 is sufficient to phenocopy pRB's ability to induce these cellular changes in cell culture experiments...
April 2, 2018: Proceedings of the National Academy of Sciences of the United States of America
L I Xiao, Yu Cao, Yang Wang, Xin Lai, Ke-Qin Gao, Pei Du, Bi-Kui Zhang, Su-Jie Jia
OBJECTIVES: To investigate whether there are aberrant acetylation modifications in global histone and monocyte chemoattractant protein-1 (MCP-1) promoter in monocytes from patients with coronary artery disease (CAD) and demonstrate the potential mechanisms. METHODS: CD14+ monocytes were isolated from 13 patients with CAD and 18 confirmed non-CAD controls using magnetic beads. Global histone H3/H4 acetylation and H3K4/H3K27 tri-methylation levels were measured with enzyme-linked immunosorbent assay...
April 2, 2018: Die Pharmazie
Kwan Yin Lee, Ziyan Chen, River Jiang, Marc D Meneghini
Set1 and Jhd2 regulate the methylation state of histone H3 lysine-4 (H3K4me) through their opposing methyltransferase and demethylase activities in the budding yeast Saccharomyces cerevisiae H3K4me associates with actively transcribed genes and, like both SET1 and JHD2 themselves, is known to regulate gene expression diversely. It remains unclear, however, if Set1 and Jhd2 act solely through H3K4me. Relevantly, Set1 methylates lysine residues in the kinetochore protein Dam1 while genetic studies of the S. pombe SET1 ortholog suggest the existence of non-H3K4 Set1 targets relevant to gene regulation...
March 29, 2018: G3: Genes—Genomes—Genetics
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