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https://www.readbyqxmd.com/read/29145444/inhibition-of-the-h3k9-methyltransferase-g9a-attenuates-oncogenicity-and-activates-the-hypoxia-signaling-pathway
#1
Jolene Caifeng Ho, Lissa Nurrul Abdullah, Qing You Pang, Sudhakar Jha, Edward Kai-Hua Chow, Henry Yang, Hiroyuki Kato, Lorenz Poellinger, Jun Ueda, Kian Leong Lee
Epigenetic mechanisms play important roles in the regulation of tumorigenesis, and hypoxia-induced epigenetic changes may be critical for the adaptation of cancer cells to the hypoxic microenvironment of solid tumors. Previously, we showed that loss-of-function of the hypoxia-regulated H3K9 methyltransferase G9A attenuates tumor growth. However, the mechanisms by which blockade of G9A leads to a tumor suppressive effect remain poorly understood. We show that G9A is highly expressed in breast cancer and is associated with poor patient prognosis, where it may function as a potent oncogenic driver...
2017: PloS One
https://www.readbyqxmd.com/read/29133140/the-histone-methyltransferase-g9a-a-new-therapeutic-target-in-biliary-tract-cancer
#2
Christian Mayr, Katharina Helm, Martin Jakab, Markus Ritter, Rajeev Shrestha, Ramesh Makaju, Andrej Wagner, Martin Pichler, Marlena Beyreis, Stefan Staettner, Tarkan Jaeger, Eckhard Klieser, Tobias Kiesslich, Daniel Neureiter
The histone methyltransferase G9a (EHMT2) is a key enzyme for dimethylation of lysine 9 at histone 3 (H3K9me2), a suppressive epigenetic mark. G9a is over-expressed in tumour cells and contributes to cancer aggressiveness. Biliary tract cancer (BTC) is a rare cancer with dismal prognosis due to a lack of effective therapies. Currently, there are no data on the role of G9a in BTC carcinogenesis. We analysed G9a expression in n=68 BTC patient specimens and correlated the data with clinico-pathological and survival data...
November 10, 2017: Human Pathology
https://www.readbyqxmd.com/read/29116191/histone-methyltransferase-g9a-is-a-key-regulator-of-the-starvation-induced-behaviors-in-drosophila-melanogaster
#3
Kouhei Shimaji, Ryo Tanaka, Toru Maeda, Mamiko Ozaki, Hideki Yoshida, Yasuyuki Ohkawa, Tetsuya Sato, Mikita Suyama, Masamitsu Yamaguchi
Organisms have developed behavioral strategies to defend themselves from starvation stress. Despite of their importance in nature, the underlying mechanisms have been poorly understood. Here, we show that Drosophila G9a (dG9a), one of the histone H3 Lys 9-specific histone methyltransferases, functions as a key regulator for the starvation-induced behaviors. RNA-sequencing analyses utilizing dG9a null mutant flies revealed that the expression of some genes relating to gustatory perception are regulated by dG9a under starvation conditions...
November 7, 2017: Scientific Reports
https://www.readbyqxmd.com/read/29115470/dimethylation-of-histone-3-lysine-9-is-sensitive-to-the-epileptic-activity-and-affects-the-transcriptional-regulation-of-the-potassium-channel-kcnj10-gene-in-epileptic-rats
#4
Shao-Ping Zhang, Man Zhang, Hong Tao, Yan Luo, Tao He, Chun-Hui Wang, Xiao-Cheng Li, Ling Chen, Lin-Na Zhang, Tao Sun, Qi-Kuan Hu
Potassium channels can be affected by epileptic seizures and serve a crucial role in the pathophysiology of epilepsy. Dimethylation of histone 3 lysine 9 (H3K9me2) and its enzyme euchromatic histone‑lysine N‑methyltransferase 2 (G9a) are the major epigenetic modulators and are associated with gene silencing. Insight into whether H3K9me2 and G9a can respond to epileptic seizures and regulate expression of genes encoding potassium channels is the main purpose of the present study. A total of 16 subtypes of potassium channel genes in pilocarpine‑modelled epileptic rats were screened by reverse transcription‑quantitative polymerase chain reaction, and it was determined that the expression ATP‑sensitive inward rectifier potassium channel 10 (Kcnj10) increased in hippocampus and insular cortex, while the expression of most of the other subtypes decreased...
November 3, 2017: Molecular Medicine Reports
https://www.readbyqxmd.com/read/29113759/pharmacological-and-transcriptional-inhibition-of-the-g9a-histone-methyltransferase-suppresses-proliferation-and-modulates-redox-homeostasis-in-human-microvascular-endothelial-cells
#5
Martyna Wojtala, Ewa Macierzyńska-Piotrowska, Dorota Rybaczek, Luciano Pirola, Aneta Balcerczyk
Epigenetic mechanisms, including histone post-translational modifications, are central regulators of cell cycle control. The euchromatic G9a histone methyltransferase (G9a HMT) is a key enzyme catalyzing histone H3 methylation on lysines 9 and 27, and its dysregulation has been linked to uncontrolled proliferation of tumor cells. Here, we have investigated the effect of G9a HMT silencing on cell proliferation of microvascular endothelial cells, a process necessary to sustain tumor growth through the formation of the vascular capillary network...
November 4, 2017: Pharmacological Research: the Official Journal of the Italian Pharmacological Society
https://www.readbyqxmd.com/read/29101051/histone-methyltransferase-g9a-modulates-hepatic-insulin-signaling-via-regulating-hmga1
#6
Weili Xue, Jin Huang, Hong Chen, Yu Zhang, Xiuqin Zhu, Jianshuang Li, Wenquan Zhang, Yangmian Yuan, Yan Wang, Ling Zheng, Kun Huang
Hepatic insulin sensitivity is critical for glucose homeostasis, and insulin resistance is a fundamental syndrome found in various metabolic disorders, including obesity and type 2 diabetes. Despite considerable studies on the mechanisms of hepatic insulin resistance, the link between epigenetic regulation and the development of insulin resistance remains elusive. Here, we reported that G9a/EHMT2, a histone methyltransferase, was markedly decreased in the liver of db/db mice and high-fat diet (HFD)-fed mice...
October 31, 2017: Biochimica et Biophysica Acta
https://www.readbyqxmd.com/read/29100324/modulation-of-the-fanconi-anemia-pathway-via-chemically-induced-changes-in-chromatin-structure
#7
David A Vierra, Jada L Garzon, Meghan A Rego, Morganne M Adroved, Maurizio Mauro, Niall G Howlett
Fanconi anemia (FA) is a rare disease characterized by congenital defects, bone marrow failure, and atypically early-onset cancers. The FA proteins function cooperatively to repair DNA interstrand crosslinks. A major step in the activation of the pathway is the monoubiquitination of the FANCD2 and FANCI proteins, and their recruitment to chromatin-associated nuclear foci. The regulation and function of FANCD2 and FANCI, however, is poorly understood. In addition, how chromatin state impacts pathway activation is also unknown...
September 29, 2017: Oncotarget
https://www.readbyqxmd.com/read/29078350/epigenetic-mechanisms-modulate-differences-in-drosophila-foraging-behavior
#8
Ina Anreiter, Jamie M Kramer, Marla B Sokolowski
Little is known about how genetic variation and epigenetic marks interact to shape differences in behavior. The foraging (for) gene regulates behavioral differences between the rover and sitter Drosophila melanogaster strains, but the molecular mechanisms through which it does so have remained elusive. We show that the epigenetic regulator G9a interacts with for to regulate strain-specific adult foraging behavior through allele-specific histone methylation of a for promoter (pr4). Rovers have higher pr4 H3K9me dimethylation, lower pr4 RNA expression, and higher foraging scores than sitters...
October 16, 2017: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/29075615/pharmacologic-targeting-of-chromatin-modulators-as-therapeutics-of-acute-myeloid-leukemia
#9
REVIEW
Rui Lu, Gang Greg Wang
Acute myeloid leukemia (AML), a common hematological cancer of myeloid lineage cells, generally exhibits poor prognosis in the clinic and demands new treatment options. Recently, direct sequencing of samples from human AMLs and pre-leukemic diseases has unveiled their mutational landscapes and significantly advanced the molecular understanding of AML pathogenesis. The newly identified recurrent mutations frequently "hit" genes encoding epigenetic modulators, a wide range of chromatin-modifying enzymes and regulatory factors involved in gene expression regulation, supporting aberration of chromatin structure and epigenetic modification as a main oncogenic mechanism and cancer-initiating event...
2017: Frontiers in Oncology
https://www.readbyqxmd.com/read/29069077/functional-convergence-of-histone-methyltransferases-ehmt1-and-kmt2c-involved-in-intellectual-disability-and-autism-spectrum-disorder
#10
Tom S Koemans, Tjitske Kleefstra, Melissa C Chubak, Max H Stone, Margot R F Reijnders, Sonja de Munnik, Marjolein H Willemsen, Michaela Fenckova, Connie T R M Stumpel, Levinus A Bok, Margarita Sifuentes Saenz, Kyna A Byerly, Linda B Baughn, Alexander P A Stegmann, Rolph Pfundt, Huiqing Zhou, Hans van Bokhoven, Annette Schenck, Jamie M Kramer
Kleefstra syndrome, caused by haploinsufficiency of euchromatin histone methyltransferase 1 (EHMT1), is characterized by intellectual disability (ID), autism spectrum disorder (ASD), characteristic facial dysmorphisms, and other variable clinical features. In addition to EHMT1 mutations, de novo variants were reported in four additional genes (MBD5, SMARCB1, NR1I3, and KMT2C), in single individuals with clinical characteristics overlapping Kleefstra syndrome. Here, we present a novel cohort of five patients with de novo loss of function mutations affecting the histone methyltransferase KMT2C...
October 2017: PLoS Genetics
https://www.readbyqxmd.com/read/29053336/interplay-between-ezh2-and-g9a-regulates-cxcl10-gene-repression-in-idiopathic-pulmonary-fibrosis
#11
William R Coward, Oliver J Brand, Alice Pasini, Gisli Jenkins, Alan J Knox, Linhua Pang
Selective repression of the antifibrotic gene CXCL10 contributes to tissue remodelling in idiopathic pulmonary fibrosis (IPF). We have previously reported that histone deacetylation and histone H3 lysine 9 (H3K9) methylation are involved in CXCL10 repression. This study explored the role of H3K27 methylation and the interplay between the two histone lysine methyltransferases, Enhancer of Zest Homolog 2 (EZH2) and G9a, in CXCL10 repression in IPF. By applying chromatin immunoprecipitation (ChIP), Re-ChIP and proximity ligation assays, we demonstrated that, like G9a-mediated H3K9 methylation, EZH2-mediated H3K27me3 was significantly enriched at the CXCL10 promoter in fibroblasts from IPF lungs (F-IPF) compared with fibroblasts from non-fibrotic lungs (F-NL) and that EZH2 and G9a physically interacted with each other...
October 20, 2017: American Journal of Respiratory Cell and Molecular Biology
https://www.readbyqxmd.com/read/29042275/basil-polysaccharide-attenuates-hepatocellular-carcinoma-metastasis-in-rat-by-suppressing-h3k9me2-histone-methylation-under-hepatic-artery-ligation-induced-hypoxia
#12
Bing Feng, Ying Zhu, Zuqing Su, Lipeng Tang, Chaoyue Sun, Caiyun Li, Guangjuan Zheng
Hepatocellular carcinoma (HCC) is one of the most common and fatal cancers in the world. Tumor metastasis is an important factor of poor prognosis in patients with HCC. Tumor hypoxia can promote tumor cell metastasis in HCC. Epigenetic modification is closely related to tumor hypoxia and metastasis. In our previous research, we found that basil polysaccharide suppressed migration and invasion of HCC cell by inhibiting hypoxia induced histone methylation in vitro. In the present study, we investigated the effect of basil polysaccharide on the walker 256 carcinoma cell metastasis in rat...
October 14, 2017: International Journal of Biological Macromolecules
https://www.readbyqxmd.com/read/28982057/effect-of-bix-01294-on-proliferation-apoptosis-and-histone-methylation-of-acute-t-lymphoblastic-leukemia-cells
#13
Yiqun Huang, Yong Zou, Luhui Lin, Xudong Ma, Xiaohong Huang
OBJECTIVE: To determine effect of G9a inhibitor BIX-01294 on proliferation, apoptosis and histone methylation of acute T lymphoblastic leukemia cells (MOLT-4 and Jurkat) and to explore the underlying mechanism. METHODS: Cell proliferation was detected by MTT assay and apoptosis and cell cycle were measured by flow cytometry. Western blot was performed to determine expression of caspase-3, Bcl-2, Bax, P21, P15 and DNMT1 as well as levels of histone H3 acetylation, histone H3K9 mono- di- and tri-methylation...
November 2017: Leukemia Research
https://www.readbyqxmd.com/read/28977928/methyltransferase-g9a-promotes-cervical-cancer-angiogenesis-and-decreases-patient-survival
#14
Ruey-Jien Chen, Chia-Tung Shun, Men-Luh Yen, Chia-Hung Chou, Ming-Chieh Lin
Research suggests that the epigenetic regulator G9a, a H3K9 histone methyltransferase, is involved in cancer invasion and metastasis. Here we show that G9a is linked to cancer angiogenesis and poor patient survival. Invasive cervical cancer has a higher G9a expression than cancer precursors or normal epithelium. Pharmacological inhibition and genetic silencing of G9a suppresses H3K9 methylation, cancer cell proliferation, angiogenesis, and cancer cell invasion/migration, but not apoptosis. Microarray and quantitative reverse transcription polymerase chain reaction analyses reveal that G9a induces a cohort of angiogenic factors that include angiogenin, interleukin-8, and C-X-C motif chemokine ligand 16...
September 22, 2017: Oncotarget
https://www.readbyqxmd.com/read/28973434/dcas9-based-epigenome-editing-suggests-acquisition-of-histone-methylation-is-not-sufficient-for-target-gene-repression
#15
Henriette O'Geen, Chonghua Ren, Charles M Nicolet, Andrew A Perez, Julian Halmai, Victoria M Le, Joel P Mackay, Peggy J Farnham, David J Segal
Distinct epigenomic profiles of histone marks have been associated with gene expression, but questions regarding the causal relationship remain. Here we investigated the activity of a broad collection of genomically targeted epigenetic regulators that could write epigenetic marks associated with a repressed chromatin state (G9A, SUV39H1, Krüppel-associated box (KRAB), DNMT3A as well as the first targetable versions of Ezh2 and Friend of GATA-1 (FOG1)). dCas9 fusions produced target gene repression over a range of 0- to 10-fold that varied by locus and cell type...
September 29, 2017: Nucleic Acids Research
https://www.readbyqxmd.com/read/28968981/structure-based-design-synthesis-and-activity-studies-of-small-hybrid-molecules-as-hdac-and-g9a-dual-inhibitors
#16
Lanlan Zang, Shukkoor M Kondengaden, Qing Zhang, Xiaobo Li, Dilep K Sigalapalli, Shameer M Kondengadan, Kenneth Huang, Keqin Kathy Li, Shanshan Li, Zhongying Xiao, Liuqing Wen, Hailiang Zhu, Bathini N Babu, Lijuan Wang, Fengyuan Che, Peng George Wang
Aberrant enzymatic activities or expression profiles of epigenetic regulations are therapeutic targets for cancers. Among these, histone 3 lysine 9 methylation (H3K9Me2) and global de-acetylation on histone proteins are associated with multiple cancer phenotypes including leukemia, prostatic carcinoma, hepatocellular carcinoma and pulmonary carcinoma. Here, we report the discovery of the first small molecule capable of acting as a dual inhibitor targeting both G9a and HDAC. Our structure based design, synthesis, and screening for the dual activity of the small molecules led to the discovery of compound 14 which displays promising inhibition of both G9a and HDAC in low micro-molar range in cell based assays...
September 8, 2017: Oncotarget
https://www.readbyqxmd.com/read/28961856/involvement-of-cryptosporidium-parvum-cdg7_flc_1000-rna-in-the-attenuation-of-intestinal-epithelial-cell-migration-via-trans-suppression-of-host-cell-smpd3-gene
#17
Zhenping Ming, Ai-Yu Gong, Yang Wang, Xin-Tian Zhang, Min Li, Nicholas W Mathy, Juliane K Strauss-Soukup, Xian-Ming Chen
Intestinal infection by Cryptosporidium parvum causes inhibition of epithelial turnover but underlying mechanisms are unclear. Previous studies demonstrate that a panel of parasite RNA transcripts of low protein-coding potential are delivered into infected epithelial cells. Using in vitro and in vivo models of intestinal cryptosporidiosis, we report here that host delivery of parasite Cdg7_Flc_1000 RNA results in inhibition of epithelial cell migration through suppression of the sphingomyelinase 3 (SMPD3) gene...
August 7, 2017: Journal of Infectious Diseases
https://www.readbyqxmd.com/read/28959017/the-whhere-coactivator-complex-is-required-for-retinoic-acid-dependent-regulation-of-embryonic-symmetry
#18
Gonçalo C Vilhais-Neto, Marjorie Fournier, Jean-Luc Plassat, Mihaela E Sardiu, Anita Saraf, Jean-Marie Garnier, Mitsuji Maruhashi, Laurence Florens, Michael P Washburn, Olivier Pourquié
Bilateral symmetry is a striking feature of the vertebrate body plan organization. Vertebral precursors, called somites, provide one of the best illustrations of embryonic symmetry. Maintenance of somitogenesis symmetry requires retinoic acid (RA) and its coactivator Rere/Atrophin2. Here, using a proteomic approach we identify a protein complex, containing Wdr5, Hdac1, Hdac2 and Rere (named WHHERE), which regulates RA signaling and controls embryonic symmetry. We demonstrate that Wdr5, Hdac1, and Hdac2 are required for RA signaling in vitro and in vivo...
September 28, 2017: Nature Communications
https://www.readbyqxmd.com/read/28956686/g9a-in-hypoxia-linking-tumor-hypoxia-and-epigenetic-regulation
#19
Francesco Casciello, Jason S Lee
No abstract text is available yet for this article.
September 28, 2017: Cell Cycle
https://www.readbyqxmd.com/read/28949961/rescuing-the-aberrant-sex-development-of-h3k9-demethylase-jmjd1a-deficient-mice-by-modulating-h3k9-methylation-balance
#20
Shunsuke Kuroki, Naoki Okashita, Shoko Baba, Ryo Maeda, Shingo Miyawaki, Masashi Yano, Miyoko Yamaguchi, Satsuki Kitano, Hitoshi Miyachi, Akihiro Itoh, Minoru Yoshida, Makoto Tachibana
Histone H3 lysine 9 (H3K9) methylation is a hallmark of heterochromatin. H3K9 demethylation is crucial in mouse sex determination; The H3K9 demethylase Jmjd1a deficiency leads to increased H3K9 methylation at the Sry locus in embryonic gonads, thereby compromising Sry expression and causing male-to-female sex reversal. We hypothesized that the H3K9 methylation level at the Sry locus is finely tuned by the balance in activities between the H3K9 demethylase Jmjd1a and an unidentified H3K9 methyltransferase to ensure correct Sry expression...
September 2017: PLoS Genetics
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