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G9a

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https://www.readbyqxmd.com/read/28532996/histone-methyltransferase-g9a-promotes-liver-cancer-development-by-epigenetic-silencing-of-tumor-suppressor-gene-rarres3
#1
Lai Wei, David Kung-Chun Chiu, Felice Ho-Ching Tsang, Dicky Cheuk-Ting Law, Carol Lai-Hung Cheng, Sandy Leung-Kuen Au, Joyce Man-Fong Lee, Carmen Chak-Lui Wong, Irene Oi-Lin Ng, Chun-Ming Wong
BACKGROUND AND AIMS: Hepatocellular carcinoma (HCC) is a major leading cause of cancer mortality worldwide. Epigenetic deregulation is a common trait of human HCC. G9s is an important epigenetics regulator. However, its roles in liver carcinogenesis remain to be investigated. METHODS: Gene expressions were determined by RNA-Seq and qRT-PCR. G9a knockdown and knockout cell lines were established by lentiviral-based shRNA and CRISPR/Cas9 gene editing system. Tumor promoting functions of G9a was studied by both in HCC cell lines and nude mice model...
May 19, 2017: Journal of Hepatology
https://www.readbyqxmd.com/read/28527696/essential-roles-of-g9a-in-cell-proliferation-and-differentiation-during-tooth-development
#2
Taichi Kamiunten, Hisashi Ideno, Akemi Shimada, Yoshinori Arai, Tatsuo Terashima, Yasuhiro Tomooka, Yoshiki Nakamura, Kazuhisa Nakashima, Hiroshi Kimura, Yoichi Shinkai, Makoto Tachibana, Akira Nifuji
Teeth develop through interactions between epithelial and mesenchymal tissues mediated by a signaling network comprised of growth factors and transcription factors However, little is known about how epigenetic modifiers affect signaling pathways and thereby regulate tooth formation. We previously reported that the histone 3 lysine 9 (H3K9) methyltransferase (MTase) G9a is specifically enriched in the tooth mesenchyme during mouse development. In this study, we investigated the functions of G9a in tooth development using G9a conditional knockout (KO) mice...
May 17, 2017: Experimental Cell Research
https://www.readbyqxmd.com/read/28525743/bromodomain-protein-brd4-is-a-transcriptional-repressor-of-autophagy-and-lysosomal-function
#3
Jun-Ichi Sakamaki, Simon Wilkinson, Marcel Hahn, Nilgun Tasdemir, Jim O'Prey, William Clark, Ann Hedley, Colin Nixon, Jaclyn S Long, Maria New, Tim Van Acker, Sharon A Tooze, Scott W Lowe, Ivan Dikic, Kevin M Ryan
Autophagy is a membrane-trafficking process that directs degradation of cytoplasmic material in lysosomes. The process promotes cellular fidelity, and while the core machinery of autophagy is known, the mechanisms that promote and sustain autophagy are less well defined. Here we report that the epigenetic reader BRD4 and the methyltransferase G9a repress a TFEB/TFE3/MITF-independent transcriptional program that promotes autophagy and lysosome biogenesis. We show that BRD4 knockdown induces autophagy in vitro and in vivo in response to some, but not all, situations...
May 18, 2017: Molecular Cell
https://www.readbyqxmd.com/read/28483947/regulation-of-usp37-expression-by-rest-associated-g9a-dependent-histone-methylation
#4
Tara Dobson, Rashieda J Hatcher, Jyothismathi Swaminathan, Chandra M Das, Shavali Shaik, Rong-Hua Tao, Ciro Milite, Sabrina Castellano, Pete Taylor, Gianluca Sbardella, Vidya Gopalakrishnan
The deubiquitylase (DUB) USP37 is a component of the ubiquitin system and controls cell proliferation by regulating the stability of the cyclin-dependent kinase inhibitor 1B, (CDKN1B/p27Kip1). The expression of USP37 is down-regulated in human medulloblastoma tumor specimens. In the current study we show that USP37 prevents medulloblastoma growth in mouse orthotopic models, suggesting that it has tumor suppressive properties in this neural cancer. Here, we also report on the mechanism underlying USP37 loss in medulloblastoma...
May 8, 2017: Molecular Cancer Research: MCR
https://www.readbyqxmd.com/read/28481620/ifn%C3%AE-influences-epithelial-anti-viral-responses-via-histone-methylation-of-the-rig-i-promoter
#5
C Mirella Spalluto, Akul Singhania, Doriana Cellura, Christopher H Woelk, Tilman Sanchez-Elsner, Karl J Staples, Tom M A Wilkinson
The asthmatic lung is prone to respiratory viral infections that exacerbate the symptoms of the underlying disease. Recent work has suggested that a deficient Th1 response in early life may lead to these aberrant anti-viral responses. We investigated whether the inflammatory environment of the airway epithelium could modulate anti-viral gene expression via epigenetic mechanisms, in order to study the development of a long-term dysregulation of innate responses, which are a hallmark of asthma. We primed AALEB, a human bronchial epithelial cell line, with IFNγ and IL13 and subsequently infected cells with Respiratory Syncytial Virus (RSV) and innate anti-viral genes expression and their epigenetic markers were analysed...
May 8, 2017: American Journal of Respiratory Cell and Molecular Biology
https://www.readbyqxmd.com/read/28462942/cell-type-specific-epigenetic-editing-at-the-fosb-gene-controls-susceptibility-to-social-defeat-stress
#6
Peter J Hamilton, Dominika J Burek, Sonia I Lombroso, Rachael L Neve, Alfred J Robison, Eric J Nestler, Elizabeth A Heller
Chronic social defeat stress regulates the expression of Fosb in the nucleus accumbens (NAc) to promote the cell-type specific accumulation of ΔFosB in the two medium spiny neuron (MSN) subtypes in this region. ΔFosB is selectively induced in D1-MSNs in the NAc of resilient mice, and in D2-MSNs of susceptible mice. However, little is known about the consequences of such selective induction, particularly in D2-MSNs. This study examined how cell-type specific control of the endogenous Fosb gene in NAc regulates susceptibility to social defeat stress...
May 2, 2017: Neuropsychopharmacology: Official Publication of the American College of Neuropsychopharmacology
https://www.readbyqxmd.com/read/28460359/synthesis-and-biological-evaluation-of-benzimidazole-derivatives-as-the-g9a-histone-methyltransferase-inhibitors-that-induce-autophagy-and-apoptosis-of-breast-cancer-cells
#7
Jin Zhang, Dahong Yao, Yingnan Jiang, Jian Huang, Shilin Yang, Jinhui Wang
G9a (also known as KMT1C or EHMT2) is initially identified as a H3K9 methyltransferase that specifically mono- and dimethylates 'Lys-9' of histone H3 (H3K9me1 and H3K9me2, respectively) in euchromatin. It is overexpressed in various human cancers and employed as a promising target in cancer therapy. We discovered a benzoxazole scaffold through virtual high-throughput screening, and designed, synthesized 24 derivatives and investigated for inhibition of G9a. After several rounds of kinase and anti-proliferative activity screening, we discovered a potent G9a antagonist (GA001) with an IC50 value of 1...
April 17, 2017: Bioorganic Chemistry
https://www.readbyqxmd.com/read/28457889/2i-maintains-a-naive-ground-state-in-escs-through-two-distinct-epigenetic-mechanisms
#8
Ye-Ji Sim, Min-Seong Kim, Abeer Nayfeh, Ye-Jin Yun, Su-Jin Kim, Kyung-Tae Park, Chang-Hoon Kim, Kye-Seong Kim
Mouse embryonic stem cells (ESCs) are maintained in serum with leukemia inhibitory factor (LIF) to maintain self-renewal and pluripotency. Recently, a 2i culture method was reported using a combination of MEK inhibition (MEKi) and GSK3 inhibition (GSK3i) with LIF to maintain ESCs in a naive ground state. How 2i maintains a ground state of ESCs remains elusive. Here we show that MEKi and GSK3i maintain the ESC ground state by downregulating global DNA methylation through two distinct mechanisms. MEK1 phosphorylates JMJD2C for ubiquitin-mediated protein degradation...
May 9, 2017: Stem Cell Reports
https://www.readbyqxmd.com/read/28455378/ehmt2-g9a-controls-placental-vascular-maturation-by-activating-the-notch-pathway
#9
Lijun Chi, Abdalla Ahmed, Anna R Roy, Sandra Vuong, Lindsay S Cahill, Laura Caporiccio, John G Sled, Isabella Caniggia, Michael D Wilson, Paul Delgado-Olguin
Defective fetoplacental vascular maturation causes intrauterine growth restriction (IUGR). A transcriptional switch initiates placental maturation where blood vessels elongate. However, cellular mechanisms and regulatory pathways involved are unknown. We show that the histone methyltransferase Ehmt2, also known as G9a, activates the Notch pathway to promote placental vascular maturation. Placental vasculature from embryos with G9a-deficient endothelial progenitor cells failed to expand due to decreased endothelial cell proliferation and increased trophoblast proliferation...
April 28, 2017: Development
https://www.readbyqxmd.com/read/28445939/epigenetic-therapy-with-inhibitors-of-histone-methylation-suppresses-dna-damage-signaling-and-increases-glioma-cell-radiosensitivity
#10
Ozge Gursoy-Yuzugullu, Chelsea Carman, Rodolfo Bortolozo Serafim, Marios Myronakis, Valeria Valente, Brendan D Price
Radiation therapy is widely used to treat human malignancies, but many tumor types, including gliomas, exhibit significant radioresistance. Radiation therapy creates DNA double-strand breaks (DSBs), and DSB repair is linked to rapid changes in epigenetic modifications, including increased histone methylation. This increased histone methylation recruits DNA repair proteins which can then alter the local chromatin structure and promote repair. Consequently, combining inhibitors of specific histone methyltransferases with radiation therapy may increase tumor radiosensitivity, particularly in tumors with significant therapeutic resistance...
April 11, 2017: Oncotarget
https://www.readbyqxmd.com/read/28443098/the-lysine-methyltransferase-g9a-in-immune-cell-differentiation-and-function
#11
REVIEW
Sebastian Scheer, Colby Zaph
G9a (KMT1C, EHMT2) is a lysine methyltransferase (KMT) whose primary function is to di-methylate lysine 9 of histone H3 (H3K9me2). G9a-dependent H3K9me2 is associated with gene silencing and acts primarily through the recruitment of H3K9me2-binding proteins that prevent transcriptional activation. Gene repression via G9a-dependent H3K9me2 is critically required in embryonic stem (ES) cells for the development of cellular lineages by repressing expression of pluripotency factors. In the immune system, lymphoid cells such as T cells and innate lymphoid cells (ILCs) can differentiate from a naïve state into one of several effector lineages that require both activating and repressive mechanisms to maintain the correct gene expression program...
2017: Frontiers in Immunology
https://www.readbyqxmd.com/read/28423509/histone-lysine-methyltransferase-g9a-is-a-novel-epigenetic-target-for-the-treatment-of-hepatocellular-carcinoma
#12
Masayuki Yokoyama, Tetsuhiro Chiba, Yoh Zen, Motohiko Oshima, Yuko Kusakabe, Yoshiko Noguchi, Kaori Yuki, Shuhei Koide, Shiro Tara, Atsunori Saraya, Kazumasa Aoyama, Naoya Mimura, Satoru Miyagi, Masanori Inoue, Toru Wakamatsu, Tomoko Saito, Sadahisa Ogasawara, Eiichiro Suzuki, Yoshihiko Ooka, Akinobu Tawada, Masayuki Otsuka, Masaru Miyazaki, Osamu Yokosuka, Atsushi Iwama
Histone H3 lysine 9 dimethylation (H3K9me2) is mainly regulated by the histone lysine methyltransferase G9a and is associated with the repression of transcription. However, both the role of G9a and the significance of H3K9me2 in hepatocellular carcinoma (HCC) cells remain unclear. In this study, we conducted loss-of-function assay of G9a using short-hairpin RNA and pharmacological interference. Knockdown of G9a reduced H3K9me2 levels and impaired both HCC cell growth and sphere formation. However, transforming growth factor β1-induced epithelial mesenchymal transition (EMT) was not suppressed by G9a knockdown...
March 28, 2017: Oncotarget
https://www.readbyqxmd.com/read/28402439/chromodomain-protein-cdyl-is-required-for-transmission-restoration-of-repressive-histone-marks
#13
Yongqing Liu, Shumeng Liu, Shuai Yuan, Huajing Yu, Yu Zhang, Xiaohan Yang, Guojia Xie, Zhe Chen, Wanjin Li, Bosen Xu, Luyang Sun, Yongfeng Shang, Jing Liang
Faithful transmission or restoration of epigenetic information such as repressive histone modifications through generations is critical for the maintenance of cell identity. We report here that chromodomain Y-like protein (CDYL), a chromodomain-containing transcription corepressor, is physically associated with chromatin assembly factor 1 (CAF-1) and the replicative helicase MCM complex. We showed that CDYL bridges CAF-1 and MCM, facilitating histone transfer and deposition during DNA replication. We demonstrated that CDYL recruits histone-modifying enzymes G9a, SETDB1, and EZH2 to replication forks, leading to the addition of H3K9me2/3 and H3K27me2/3 on newly deposited histone H3...
April 10, 2017: Journal of Molecular Cell Biology
https://www.readbyqxmd.com/read/28387360/regulatory-role-of-g9a-and-lsd1-in-the-transcription-of-olfactory-receptors-during-leukaemia-cell-differentiation
#14
Hyeonsoo Jung, Yun-Cheol Chae, Ji-Young Kim, Oh-Seok Jeong, Hoon Kook, Sang-Beom Seo
Recent studies have reported the ectopic expression of olfactory receptors (ORs) in non-olfactory tissues, however, their physiological roles were not well elucidated. ORs are expressed in and function in different types of cancers. Here, we identified that the H3K9me2 levels of several OR promoters decreased during differentiation in the HL-60, human myeloid leukaemia cell line, by all-trans-retinoic acid (ATRA). We found that the differential OR promoters H3K9me2 levels were regulated by G9a and LSD1, resulting in the decrease of ORs transcription during HL-60 differentiation...
April 7, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28383547/g9a-promotes-tumor-cell-growth-and-invasion-by-silencing-casp1-in-non-small-cell-lung-cancer-cells
#15
Tianhao Huang, Peng Zhang, Wang Li, Tian Zhao, Zhixiong Zhang, Sujun Chen, Yan Yang, Yonghong Feng, Fei Li, X Shirley Liu, Lei Zhang, Gening Jiang, Fan Zhang
Non-small-cell lung cancer (NSCLC) is one of the leading causes of cancer-related death worldwide. Although epigenetic deregulation is known to be important for tumor progression, the molecular mechanisms in NSCLC remain unclear. Here, we found that G9A (known as EHMT2), a histone methyltransferase responsible for mono- or di-methylation of histone 3 (H3) lysine 9 (K9), is significantly upregulated in NSCLC. Knocking down G9A or pharmacological inhibition of its activity suppressed tumor cell growth, colony formation, invasion and migration...
April 6, 2017: Cell Death & Disease
https://www.readbyqxmd.com/read/28361100/a-novel-de-novo-frameshift-deletion-in-ehmt1-in-a-patient-with-kleefstra-syndrome-results-in-decreased-h3k9-dimethylation
#16
Patrick R Blackburn, Monique Williams, Margot A Cousin, Nicole J Boczek, Geoffrey J Beek, Gwen A Lomberk, Raul A Urrutia, Dusica Babovic-Vuksanovic, Eric W Klee
BACKGROUND: Kleefstra Syndrome (KS) (MIM# 610253) is an autosomal dominant disorder caused by haploinsufficiency of euchromatic histone methyltransferase-1 (EHMT1, GLP). EHMT1 (MIM# 607001) encodes a histone methyltransferase that heterodimerizes with EHMT2 (also known as G9a, MIM# 604599), which together are responsible for mono- and dimethylation of H3 lysine 9 (H3K9me1 and -me2), resulting in transcriptional repression of target genes. METHODS: This report describes an 18-year-old woman with intellectual disability, severely limited speech, hypotonia, microcephaly, and facial dysmorphisms, who was found to have a novel de novo single-base frameshift deletion in EHMT1...
March 2017: Molecular Genetics & Genomic Medicine
https://www.readbyqxmd.com/read/28351524/g9a-governs-colon-cancer-stem-cell-phenotype-and-chemoradioresistance-through-pp2a-rpa-axis-mediated-dna-damage-response
#17
Chi-Wen Luo, Jaw-Yuan Wang, Wen-Chun Hung, Guang Peng, Ya-Li Tsai, Tsung-Ming Chang, Chee-Yin Chai, Chih-Hung Lin, Mei-Ren Pan
BACKGROUND AND PURPOSE: Neoadjuvant concurrent chemoradiotherapy (CCRT) is a standard treatment of locally advanced colon cancer cell (CRC). In order to maximize efficacy and minimize toxicity, new drugs have been developed and used in combination with CCRT. Recently, it has been shown that G9a plays a role in mediating phenotypes of cancer stem cells (CSCs). This study aimed to characterize G9a as a biomarker in predicting therapy response to prevent overtreatment and adverse effects in CRC patients...
March 25, 2017: Radiotherapy and Oncology: Journal of the European Society for Therapeutic Radiology and Oncology
https://www.readbyqxmd.com/read/28327608/kdm4b-histone-demethylase-and-g9a-regulate-expression-of-vascular-adhesion-proteins-in-cerebral-microvessels
#18
Ji-Young Choi, Sang-Sun Yoon, Sang-Eun Kim, Sangmee Ahn Jo
Intercellular adhesion molecule 1 (ICAM1) mediates the adhesion and transmigration of leukocytes across the endothelium, promoting inflammation. We investigated the epigenetic mechanism regulating ICAM1 expression. The pro-inflammatory cytokine TNF-α dramatically increased ICAM1 mRNA and protein levels in human brain microvascular endothelial cells and mouse brain microvessels. Chromatin immunoprecipitation revealed that TNF-α reduced methylation of histone H3 at lysines 9 and 27 (H3K9 and H3K27), well-known residues involved in gene suppression...
March 22, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28301528/genome-wide-mapping-of-histone-h3k9me2-in-acute-myeloid-leukemia-reveals-large-chromosomal-domains-associated-with-massive-gene-silencing-and-sites-of-genome-instability
#19
Anna C Salzberg, Abigail Harris-Becker, Evgenya Y Popova, Nikki Keasey, Thomas P Loughran, David F Claxton, Sergei A Grigoryev
A facultative heterochromatin mark, histone H3 lysine 9 dimethylation (H3K9me2), which is mediated by histone methyltransferases G9a/GLP (EHMT2/1), undergoes dramatic rearrangements during myeloid cell differentiation as observed by chromatin imaging. To determine whether these structural transitions also involve genomic repositioning of H3K9me2, we used ChIP-sequencing to map genome-wide topography of H3K9me2 in normal human granulocytes, normal CD34+ hematopoietic progenitors, primary myeloblasts from acute myeloid leukemia (AML) patients, and a model leukemia cell line K562...
2017: PloS One
https://www.readbyqxmd.com/read/28278257/inhibition-of-h3k9-methyltransferase-g9a-ameliorates-methylglyoxal-induced-peritoneal-fibrosis
#20
Kazuya Maeda, Shigehiro Doi, Ayumu Nakashima, Takuo Nagai, Taisuke Irifuku, Toshinori Ueno, Takao Masaki
Activity of H3K9 histone methyltransferase G9a is reportedly induced by transforming growth factor-β1 (TGF-β1) and plays an important role in the progression of cancer and fibrosis. In this study, we investigated whether inhibition of G9a-mediated H3K9 methylation attenuates peritoneal fibrosis in mice and human peritoneal mesothelial cells (HPMCs). Nonadherent cells of peritoneal dialysis (PD) patients were isolated from PD effluent to examine expression of G9a. Peritoneal fibrosis was induced by peritoneal injection of methylglyoxal (MGO) in male C57/B6 mice for 3 weeks...
2017: PloS One
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