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https://www.readbyqxmd.com/read/29769286/targeted-inhibition-of-histone-h3k27-demethylation-is-effective-in-high-risk-neuroblastoma
#1
Timothy L Lochmann, Krista M Powell, Jungoh Ham, Konstantinos V Floros, Daniel A R Heisey, Richard I J Kurupi, Marissa L Calbert, Maninderjit S Ghotra, Patricia Greninger, Mikhail Dozmorov, Madhu Gowda, Andrew J Souers, C Patrick Reynolds, Cyril H Benes, Anthony C Faber
High-risk neuroblastoma is often distinguished by amplification of MYCN and loss of differentiation potential. We performed high-throughput drug screening of epigenetic-targeted therapies across a large and diverse tumor cell line panel and uncovered the hypersensitivity of neuroblastoma cells to GSK-J4, a small-molecule dual inhibitor of lysine 27 of histone 3 (H3K27) demethylases ubiquitously transcribed tetratricopeptide repeat, X chromosome (UTX), and histone demethylase Jumonji D3 (JMJD3). Mechanistically, GSK-J4 induced neuroblastoma differentiation and endoplasmic reticulum (ER) stress, with accompanying up-regulation of p53 up-regulated modulator of apoptosis (PUMA) and induction of cell death...
May 16, 2018: Science Translational Medicine
https://www.readbyqxmd.com/read/29753027/jmjd3-inhibition-protects-against-isoproterenol-induced-cardiac-hypertrophy-by-suppressing-%C3%AE-mhc-expression
#2
Zhen Guo, Jing Lu, Jingyan Li, Panxia Wang, Zhenzhen Li, Yao Zhong, Kaiteng Guo, Junjian Wang, Jiantao Ye, Peiqing Liu
Jumonji domain-containing protein D3 (JMJD3), a histone 3 lysine 27 (H3K27) demethylase, has been extensively studied for their participation in development, cellular physiology and a variety of diseases. However, its potential roles in cardiovascular system remain unknown. In this study, we found that JMJD3 played a pivotal role in the process of cardiac hypertrophy. JMJD3 expression was elevated by isoproterenol (ISO) stimuli both in vitro and in vivo. Overexpression of wild-type JMJD3, but not the demethylase-defective mutant, promoted cardiomyocyte hypertrophy, as implied by increased cardiomyocyte surface area and the expression of hypertrophy marker genes...
May 9, 2018: Molecular and Cellular Endocrinology
https://www.readbyqxmd.com/read/29622035/ccl17-blockade-as-a-therapy-for-osteoarthritis-pain-and-disease
#3
Ming-Chin Lee, Reem Saleh, Adrian Achuthan, Andrew J Fleetwood, Irmgard Förster, John A Hamilton, Andrew D Cook
BACKGROUND: Granulocyte macrophage-colony stimulating factor (GM-CSF) has been implicated in the pathogenesis of a number of inflammatory diseases and in osteoarthritis (OA). We identified previously a new GM-CSF→Jmjd3→interferon regulatory factor 4 (IRF4)→chemokine (c-c motif) ligand 17 (CCL17) pathway, which is important for the development of inflammatory arthritis pain and disease. Tumour necrosis factor (TNF) can also be linked with this pathway. Here we investigated the involvement of the pathway in OA pain and disease development using the GM-CSF-dependent collagenase-induced OA (CiOA) model...
April 5, 2018: Arthritis Research & Therapy
https://www.readbyqxmd.com/read/29621735/jmjd3-is-involved-in-neutrophil-membrane-proteinase-3-overexpression-during-the-hyperinflammatory-response-in-early-sepsis
#4
Yang Chen, Zhaojun Liu, Tingting Pan, Erzhen Chen, Enqiang Mao, Ying Chen, Ruoming Tan, Xiaoli Wang, Rui Tian, Jialin Liu, Hongping Qu
Excessive production of pro-inflammatory cytokines in early sepsis causes high early mortality rates. Membrane proteinase 3 (mPR3) expression on neutrophils plays a critical role in pro-inflammatory cytokine production. However, the mechanism underlying mPR3 overexpression in early sepsis is unknown. Here, we explored mPR3 expression in early sepsis and its regulatory mechanism. Thirty-two patients with sepsis and 20 healthy controls were prospectively enrolled. On day 1 after the onset of sepsis, mPR3 and jumonji domain-containing protein D3 (JMJD3) expression levels were measured in peripheral blood neutrophils...
April 2, 2018: International Immunopharmacology
https://www.readbyqxmd.com/read/29609686/aberrant-histone-modifications-of-global-histone-and-mcp-1-promoter-in-cd14-monocytes-from-patients-with-coronary-artery-disease
#5
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
https://www.readbyqxmd.com/read/29594337/therapeutic-potential-of-gsk-j4-a-histone-demethylase-kdm6b-jmjd3-inhibitor-for-acute-myeloid-leukemia
#6
Yunan Li, Mingying Zhang, Mengyao Sheng, Peng Zhang, Zizhen Chen, Wen Xing, Jie Bai, Tao Cheng, Feng-Chun Yang, Yuan Zhou
PURPOSE: Acute myeloid leukemia (AML) is a heterogeneous disease with poor outcomes. Despite increased evidence shows that dysregulation of histone modification contributes to AML, specific drugs targeting key histone modulators are not applied in the clinical treatment of AML. Here, we investigated whether targeting KDM6B, the demethylase of tri-methylated histone H3 lysine 27 (H3K27me3), has a therapeutic potential for AML. METHODS: A KDM6B-specific inhibitor, GSK-J4, was applied to treat the primary cells from AML patients and AML cell lines in vitro and in vivo...
March 28, 2018: Journal of Cancer Research and Clinical Oncology
https://www.readbyqxmd.com/read/29563337/tnf-and-granulocyte-macrophage-colony-stimulating-factor-interdependence-mediates-inflammation-via-ccl17
#7
Andrew D Cook, Ming-Chin Lee, Reem Saleh, Hsu-Wei Khiew, Anne D Christensen, Adrian Achuthan, Andrew J Fleetwood, Derek C Lacey, Julia E Smith, Irmgard Förster, John A Hamilton
TNF and granulocyte macrophage-colony stimulating factor (GM-CSF) have proinflammatory activity and both contribute, for example, to rheumatoid arthritis pathogenesis. We previously identified a new GM-CSF→JMJD3 demethylase→interferon regulatory factor 4 (IRF4)→CCL17 pathway that is active in monocytes/macrophages in vitro and important for inflammatory pain, as well as for arthritic pain and disease. Here we provide evidence for a nexus between TNF and this pathway, and for TNF and GM-CSF interdependency...
March 22, 2018: JCI Insight
https://www.readbyqxmd.com/read/29559448/dynamics-of-chromatin-marks-and-the-role-of-jmjd3-during-pancreatic-endocrine-cell-fate-commitment
#8
Xin-Xin Yu, Wei-Lin Qiu, Liu Yang, Lin-Chen Li, Yu-Wei Zhang, Cheng-Ran Xu
Pancreatic endocrine lineages are derived from pancreatic progenitors that undergo a cell fate transition requiring a switch from low to high Ngn3 expression. However, the underlying chromatin regulatory mechanisms are unclear. Here, we performed epigenomic analysis of gene regulatory loci featuring histone marks in cells with low or high level of Ngn3 expression. In combination with transcriptomic analysis, we discovered that in Ngn3-high cells, the removal of H3K27me3 was associated with the activation of key transcription factors and the establishment of primed and active enhancers...
March 20, 2018: Development
https://www.readbyqxmd.com/read/29542684/exosomes-from-suxiao-jiuxin-pill-treated-cardiac-mesenchymal-stem-cells-decrease-h3k27-demethylase-utx-expression-in-mouse-cardiomyocytes-in-vitro
#9
Xiao-Fen Ruan, Yong-Jun Li, Cheng-Wei Ju, Yan Shen, Wei Lei, Can Chen, Yang Li, Hong Yu, Yu-Tao Liu, Il-Man Kim, Xiao-Long Wang, Neal L Weintraub, Yao-Liang Tang
Suxiao Jiuxin Pill (SJP) is a traditional Chinese medicine for the treatment of acute coronary syndrome in China, which contains two principal components, tetramethylpyrazine (TMP) and borneol (BOR). Thus far, however, the molecular mechanisms underlying the beneficial effects of SJP on the cardiac microenvironment are unknown. Cardiac mesenchymal stem cells (C-MSCs) communicate with cardiomyocytes (CMs) through the release of microvesicles (exosomes) to restore cardiac homeostasis and elicit repair, in part through epigenetic regulatory mechanisms...
March 15, 2018: Acta Pharmacologica Sinica
https://www.readbyqxmd.com/read/29530603/modulation-of-the-endocrine-transcriptional-program-by-targeting-histone-modifiers-of-the-h3k27me3-mark
#10
Marta Fontcuberta-PiSunyer, Sara Cervantes, Eulàlia Miquel, Sergio Mora-Castilla, Louise C Laurent, Angel Raya, Ramon Gomis, Rosa Gasa
Posttranscriptional modifications of histones constitute an epigenetic mechanism that is closely linked to both gene silencing and activation events. Trimethylation of Histone3 at lysine 27 (H3K27me3) is a repressive mark that associates with developmental gene regulation during differentiation programs. In the developing pancreas, expression of the transcription factor Neurogenin3 in multipotent progenitors initiates endocrine differentiation that culminates in the generation of all pancreatic islet cell lineages, including insulin-producing beta cells...
March 9, 2018: Biochimica et Biophysica Acta
https://www.readbyqxmd.com/read/29481307/histone-demethylase-jmjd3-regulates-fibroblast-like-synoviocyte-mediated-proliferation-and-joint-destruction-in-rheumatoid-arthritis
#11
Wanwan Jia, Weijun Wu, Di Yang, Chenxi Xiao, Zhenghua Su, Zheng Huang, Zhongzheng Li, Ming Qin, Mengwei Huang, Siyu Liu, Fen Long, Xinhua Liu, Yi Zhun Zhu
Rheumatoid arthritis (RA) is an immune-mediated disease with the characteristics of progressive joint destruction, deformity, and disability. Epigenetic changes have been implicated in the development of some autoimmune disorders, resulting in an alteration of gene transcription. Here, we investigated how Jumonji C family of histone demethylases (JMJD3) regulated the proliferation and activation of fibroblast-like synoviocytes (FLSs), which are involved in RA joint destruction and pathologic process. The JMJD3 expression and proliferation markers in RA-FLS were higher than those in healthy-FLS and were upregulated in platelet-derived growth factor (PDGF)-induced FLS...
February 26, 2018: FASEB Journal: Official Publication of the Federation of American Societies for Experimental Biology
https://www.readbyqxmd.com/read/29438503/lineage-specific-transcription-factors-and-epigenetic-regulators-mediate-tgf%C3%AE-dependent-enhancer-activation
#12
Raquel Fueyo, Simona Iacobucci, Stella Pappa, Conchi Estarás, Sergio Lois, Marta Vicioso-Mantis, Claudia Navarro, Sara Cruz-Molina, José Carlos Reyes, Álvaro Rada-Iglesias, Xavier de la Cruz, Marian A Martínez-Balbás
During neurogenesis, dynamic developmental cues, transcription factors and histone modifying enzymes regulate the gene expression programs by modulating the activity of neural-specific enhancers. How transient developmental signals coordinate transcription factor recruitment to enhancers and to which extent chromatin modifiers contribute to enhancer activity is starting to be uncovered. Here, we take advantage of neural stem cells as a model to unravel the mechanisms underlying neural enhancer activation in response to the TGFβ signaling...
February 9, 2018: Nucleic Acids Research
https://www.readbyqxmd.com/read/29378332/the-histone-demethylase-jmjd3-regulates-zebrafish-myeloid-development-by-promoting-spi1-expression
#13
Shan-He Yu, Kang-Yong Zhu, Fan Zhang, Juan Wang, Hao Yuan, Yi Chen, Yi Jin, Mei Dong, Lei Wang, Xiao-E Jia, Lei Gao, Zhi-Wei Dong, Chun-Guang Ren, Li-Ting Chen, Qiu-Hua Huang, Min Deng, Leonard I Zon, Yi Zhou, Jiang Zhu, Peng-Fei Xu, Ting-Xi Liu
The histone demethylase Jmjd3 plays a critical role in cell lineage specification and differentiation at various stages of development. However, its function during normal myeloid development remains poorly understood. Here, we carried out a systematic in vivo screen of epigenetic factors for their function in hematopoiesis and identified Jmjd3 as a new epigenetic factor that regulates myelopoiesis in zebrafish. We demonstrated that jmjd3 was essential for zebrafish primitive and definitive myelopoiesis, knockdown of jmjd3 suppressed the myeloid commitment and enhanced the erythroid commitment...
February 2018: Biochimica et Biophysica Acta
https://www.readbyqxmd.com/read/29301935/inhibition-of-histone-h3k27-demethylases-selectively-modulates-inflammatory-phenotypes-of-natural-killer-cells
#14
Adam Cribbs, Edward S Hookway, Graham Wells, Morten Lindow, Susanna Obad, Henrik Oerum, Rab K Prinjha, Nick Athanasou, Aneka Sowman, Martin Philpott, Henry Penn, Kalle Soderstrom, Marc Feldmann, Udo Oppermann
Natural killer (NK) cells are innate lymphocytes, important in immune surveillance and elimination of stressed, transformed, or virus-infected cells. They critically shape the inflammatory cytokine environment to orchestrate interactions of cells of the innate and adaptive immune systems. Some studies have reported that NK cell activation and cytokine secretion are controlled epigenetically but have yielded only limited insight into the mechanisms. Using chemical screening with small-molecule inhibitors of chromatin methylation and acetylation, further validated by knockdown approaches, we here identified Jumonji-type histone H3K27 demethylases as key regulators of cytokine production in human NK cell subsets...
February 16, 2018: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/29247011/histone-demethylase-activity-of-utx-is-essential-for-viability-and-regulation-of-hox-gene-expression-in-drosophila
#15
Ömer Copur, Jürg Müller
The trimethylation of histone H3 at lysine 27 (H3K27me3) by Polycomb Repressive Complex 2 (PRC2) is essential for the repression of Polycomb target genes. However, the role of enzymatic demethylation of H3K27me3 by the KDM6-family demethylases Utx, Uty, and JmjD3 is less clear. Studies in both mice and worms led to the proposal that KDM6 proteins, but not their H3K27me3 demethylase activity, is critical for normal development. Here, we investigated the requirement of the demethylase activity of the single KDM6 family member Utx in Drosophila We generated Drosophila expressing a full-length but catalytically inactive Utx protein and found that these mutants show the same phenotypes as animals lacking the Utx protein...
February 2018: Genetics
https://www.readbyqxmd.com/read/29245970/calcitriol-induces-cell-senescence-of-kidney-cancer-through-jmjd3-mediated-histone-demethylation
#16
Yongqing Shen, Dan Yu, Pan Qi, Xuliang Wang, Xiaoqiang Guo, Aili Zhang
Calcitriol, also known as 1,25-dihydroxyvitamin D3 (1,25(OH)2 VD3 ), is a biologically active form of vitamin D and has a wide range of anticancer activity against various cancer cell lines. However, the mechanism of calcitriol remains to be further studied. In this study, the biological effect and epigenetic regulation of calcitriol on kidney cancer cells were investigated. Calcitriol can significantly inhibit cell proliferation of kidney cancer cell lines 786-O ( P <0.05). Calcitriol also induced cell apoptosis and senescence of 786-O and ACHN ( P <0...
November 21, 2017: Oncotarget
https://www.readbyqxmd.com/read/29227285/shifts-in-podocyte-histone-h3k27me3-regulate-mouse-and-human-glomerular-disease
#17
Syamantak Majumder, Karina Thieme, Sri N Batchu, Tamadher A Alghamdi, Bridgit B Bowskill, M Golam Kabir, Youan Liu, Suzanne L Advani, Kathryn E White, Laurette Geldenhuys, Karthik K Tennankore, Penelope Poyah, Ferhan S Siddiqi, Andrew Advani
Histone protein modifications control fate determination during normal development and dedifferentiation during disease. Here, we set out to determine the extent to which dynamic changes to histones affect the differentiated phenotype of ordinarily quiescent adult glomerular podocytes. To do this, we examined the consequences of shifting the balance of the repressive histone H3 lysine 27 trimethylation (H3K27me3) mark in podocytes. Adriamycin nephrotoxicity and subtotal nephrectomy (SNx) studies indicated that deletion of the histone methylating enzyme EZH2 from podocytes decreased H3K27me3 levels and sensitized mice to glomerular disease...
January 2, 2018: Journal of Clinical Investigation
https://www.readbyqxmd.com/read/29224413/low-hox-gene-expression-in-pml-rar%C3%AE-positive-leukemia-results-from-suppressed-histone-demethylation
#18
Katerina Rejlova, Alena Musilova, Karolina Skvarova Kramarzova, Marketa Zaliova, Karel Fiser, Meritxell Alberich-Jorda, Jan Trka, Julia Starkova
Homeobox (HOX) genes are frequently dysregulated in leukemia. Previous studies have shown that aberrant HOX gene expression accompanies leukemogenesis and affects disease progression and leukemia patient survival. Patients with acute myeloid leukemia (AML) bearing PML-RARα fusion gene have distinct HOX gene signature in comparison to other subtypes of AML patients, although the mechanism of transcription regulation is not completely understood. We previously found an association between the mRNA levels of HOX genes and those of the histone demethylases JMJD3 and UTX in PML-RARα- positive leukemia patients...
2018: Epigenetics: Official Journal of the DNA Methylation Society
https://www.readbyqxmd.com/read/29161520/ezh2-histone-methyltransferase-and-jmjd3-histone-demethylase-implications-in-prostate-cancer
#19
Mouhamed Idrissou, Marine Daures, Amani Ben Jemia, Gaëlle Judes, Khaldoun Rifaï, Frédérique Penault-Llorca, Yves-Jean Bignon, Laurent Guy, Dominique Bernard-Gallon
No abstract text is available yet for this article.
December 2017: Omics: a Journal of Integrative Biology
https://www.readbyqxmd.com/read/29074105/endogenous-hydrogen-sulfide-regulates-histone-demethylase-jmjd3-mediated-inflammatory-response-in-lps-stimulated-macrophages-and-in-a-mouse-model-of-lps-induced-septic-shock
#20
Siyu Liu, Xiling Wang, Lilong Pan, Weijun Wu, Di Yang, Ming Qin, Wanwan Jia, Chenxi Xiao, Fen Long, Junbo Ge, Xinhua Liu, YiZhun Zhu
Overproduction of inflammatory mediators contributes to uncontrolled inflammation during endotoxin shock.Cystathionine-γ-lyase (CSE), an enzyme involved in hydrogen sulfide (H2S) biosynthesis, has potential anti-inflammatory activity in a variety of inflammatory diseases. Jumonji domain-containing protein 3 (JMJD3), a histone 3 Lys27 (H3K27) demethylase, has been implicated in macrophage activation, but its function in CSE-mediated anti-inflammatory activities remains unknown. In the present study CSE was found to be upregulated in macrophages and mouse lipopolysaccharide (LPS) challenge models...
October 23, 2017: Biochemical Pharmacology
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