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Toshia R Myers, Pier Giorgio Amendola, Yvonne C Lussi, Anna Elisabetta Salcini
Post-translational modifications of histones, constitutive components of chromatin, regulate chromatin compaction and control all DNA-based cellular processes. C. elegans JMJD-1.2, a member of the KDM7 family, is a demethylase active towards several lysine residues on Histone 3 (H3), but its contribution in regulating histone methylation in germ cells has not been fully investigated. Here, we show that jmjd-1.2 is expressed abundantly in the germline where it controls the level of histone 3 lysine 9, lysine 23 and lysine 27 di-methylation (H3K9/K23/K27me2) both in mitotic and meiotic cells...
February 28, 2018: Scientific Reports
Xiaomeng Li, Gene Moon, Sook Shin, Bin Zhang, Ralf Janknecht
The E26 transformation-specific (ETS) variant 2 (ETV2) protein, also designated as ETS-related 71, is a member of the ETS transcription factor family and is essential for blood and vascular development in the embryo. The role of ETV2 in cancer has not yet been investigated. In the present study, the expression of ETV2 mRNA was identified in a variety of tumor types, including prostate carcinoma. In addition, ETV2 gene amplification was identified in several types of cancer, suggesting that ETV2 plays an oncogenic role in tumorigenesis...
January 26, 2018: Molecular Medicine Reports
Soon-Duck Ha, Woohyun Cho, Sung Ouk Kim
Anthrax lethal toxin (LeTx) is a cytotoxic virulence factor that causes cell cycle arrest and cell death in various cell types. However, susceptibility to the cytotoxic effects varies depending on cell types. In proliferating monocytes, LeTx has only transient cytotoxic effects due to activation of the phosphoinositide 3-kinase (PI3K)-AKT-mediated adaptive responses. To date, the mechanism of LeTx in activating PI3K-AKT signaling axis is unknown. This study shows that the histone deacetylase 8 (HDAC8) is involved in activating PI3K-AKT signaling axis through down-regulating the phosphatase and tensin homolog 1 (PTEN) in human monocytic THP-1 cells...
May 16, 2017: Toxins
Pier Giorgio Amendola, Nico Zaghet, João J Ramalho, Jens Vilstrup Johansen, Mike Boxem, Anna Elisabetta Salcini
The eukaryotic genome is organized in a three-dimensional structure called chromatin, constituted by DNA and associated proteins, the majority of which are histones. Post-translational modifications of histone proteins greatly influence chromatin structure and regulate many DNA-based biological processes. Methylation of lysine 36 of histone 3 (H3K36) is a post-translational modification functionally relevant during early steps of DNA damage repair. Here, we show that the JMJD-5 regulates H3K36 di-methylation and it is required at late stages of double strand break repair mediated by homologous recombination...
February 2017: PLoS Genetics
Alba Redo Riveiro, Luca Mariani, Emily Malmberg, Pier Giorgio Amendola, Juhani Peltonen, Garry Wong, Anna Elisabetta Salcini
Components of the KDM7 family of histone demethylases are implicated in neuronal development and one member, PHF8, is often found to be mutated in cases of X-linked mental retardation. However, how PHF8 regulates neurodevelopmental processes and contributes to the disease is still largely unknown. Here, we show that the catalytic activity of a PHF8 homolog in Caenorhabditis elegans , JMJD-1.2, is required non-cell-autonomously for proper axon guidance. Loss of JMJD-1.2 dysregulates transcription of the Hedgehog-related genes wrt-8 and grl-16 , the overexpression of which is sufficient to induce the axonal defects...
March 1, 2017: Development
Jianwei Zhang, Qi Li, Shaojin Zhang, Quanquan Xu, Tianen Wang
Lgr4 (leucine-rich repeat domain containing G protein-coupled receptor 4) is implicated in the transcriptional regulation of multiple histone demethylases in the progression of diverse cancers, but there are few reports concerning the molecular mechanism by which Lgr4 regulates histone demethylase activation in prostate cancer (PCa) progression. As Jmjd2a is a histone demethylase, in the current study, we investigated the relationship between interaction Lgr4 with Jmjd 2a and Jmjd2a/androgen receptor (AR) signaling pathway in PCa progression...
November 15, 2016: Experimental Cell Research
Sahana Holla, Praveen Prakhar, Vikas Singh, Anupama Karnam, Tanushree Mukherjee, Kasturi Mahadik, Pankti Parikh, Amit Singh, R S Rajmani, Subbaraya G Ramachandra, Kithiganahalli Narayanaswamy Balaji
Foamy macrophages (FM)s harbor lipid bodies that not only assist mycobacterial persistence within the granulomas but also are sites for intracellular signaling and inflammatory mediators which are essential for mycobacterial pathogenesis. However, molecular mechanisms that regulate intracellular lipid accumulation in FMs during mycobacterial infection are not clear. Here, we report for the first time that jumonji domain containing protein (JMJD)3, a demethylase of the repressive H3K27me3 mark, orchestrates the expression of M...
August 2016: PLoS Pathogens
Carsten Merkwirth, Virginija Jovaisaite, Jenni Durieux, Olli Matilainen, Sabine D Jordan, Pedro M Quiros, Kristan K Steffen, Evan G Williams, Laurent Mouchiroud, Sarah U Tronnes, Virginia Murillo, Suzanne C Wolff, Reuben J Shaw, Johan Auwerx, Andrew Dillin
Across eukaryotic species, mild mitochondrial stress can have beneficial effects on the lifespan of organisms. Mitochondrial dysfunction activates an unfolded protein response (UPR(mt)), a stress signaling mechanism designed to ensure mitochondrial homeostasis. Perturbation of mitochondria during larval development in C. elegans not only delays aging but also maintains UPR(mt) signaling, suggesting an epigenetic mechanism that modulates both longevity and mitochondrial proteostasis throughout life. We identify the conserved histone lysine demethylases jmjd-1...
May 19, 2016: Cell
Julien Vandamme, Simone Sidoli, Luca Mariani, Carsten Friis, Jesper Christensen, Kristian Helin, Ole N Jensen, Anna Elisabetta Salcini
Genome-wide analyses in Caenorhabditis elegans show that post-translational modifications (PTMs) of histones are evolutionary conserved and distributed along functionally distinct genomic domains. However, a global profile of PTMs and their co-occurrence on the same histone tail has not been described in this organism. We used mass spectrometry based middle-down proteomics to analyze histone H3 N-terminal tails from C. elegans embryos for the presence, the relative abundance and the potential cross-talk of co-existing PTMs...
November 16, 2015: Nucleic Acids Research
Nicole Rüger, Martin Roatsch, Thomas Emmrich, Henriette Franz, Roland Schüle, Manfred Jung, Andreas Link
The JumonjiC-domain-containing histone demethylase 2A (JMJD2A, KDM4A) is a key player in the epigenetic regulation of gene expression. Previous publications have shown that both elevated and lowered enzyme levels are associated with certain types of cancer, and therefore the definite role of KDM4A in oncogenesis remains elusive. To identify a novel molecular starting point with favorable physicochemical properties for the investigation of the physiological role of KDM4A, we screened a number of molecules bearing an iron-chelating moiety by using two independent assays...
November 2015: ChemMedChem
Sung Chul Kang, Se Kye Kim, Jin Choul Chai, Sun Hwa Kim, Kyoung-Jae Won, Young Seek Lee, Kyoung Hwa Jung, Young Gyu Chai
The removal of histone H3 trimethylation at lysine residue 27 (H3K27me3) plays a critical role in the transcriptional initiation of developmental genes. The H3K27me3-specific KDM6 demethylases JMJD3 and UTX are responsible for the transcriptional initiation of various developmental genes, but some genes are expressed in a KDM6 demethylase-independent manner. To address the role of H3K27me3 in the retinoic acid (RA)-induced differentiation of the human carcinoma NCCIT cell line, we inhibited JMJD3 and UTX using the H3K27me3 demethylase inhibitor GSK-J4...
2015: PloS One
Ru Zhang, Qingjun Huang, Yinpeng Li, Yang Song, Yingxue Li
OBJECTIVE: To observe the effects of Jumonji C domain-containing (JMJD) 5 depletion on colon cancer (CC). METHODS: A short-hairpin RNA targeting JMJD5 was transfected into a lentivirus to make Lv-shJMJD5 for infection into the Caco-2 human cell. Besides, a negative control shRNA was constructed. The mRNA and protein levels of JMJD5 were determined by quantitative real-time polymerase chain reaction (qRT-PCR) and western blotting, respectively. Cell proliferation, migration, and invasion were assessed by 3-(4, 5-dimethylthiazol-2-yl)-2, 5-diphenyltetrazolium bromide (MTT), soft agar colony assay and transwell assay, respectively...
2015: International Journal of Clinical and Experimental Pathology
Johnathan Labbadia, Richard I Morimoto
The heat shock response (HSR) is essential for proteostasis and cellular health. In metazoans, aging is associated with a decline in quality control, thus increasing the risk for protein conformational disease. Here, we show that in C. elegans, the HSR declines precipitously over a 4 hr period in early adulthood coincident with the onset of reproductive maturity. Repression of the HSR occurs due to an increase in H3K27me3 marks at stress gene loci, the timing of which is determined by reduced expression of the H3K27 demethylase jmjd-3...
August 20, 2015: Molecular Cell
Changrim Lee, Seokbong Hong, Min Hye Lee, Hyeon-Sook Koo
PHF8 is a JmjC domain-containing histone demethylase, defects in which are associated with X-linked mental retardation. In this study, we examined the roles of two PHF8 homologs, JMJD-1.1 and JMJD-1.2, in the model organism C. elegans in response to DNA damage. A deletion mutation in either of the genes led to hypersensitivity to interstrand DNA crosslinks (ICLs), while only mutation of jmjd-1.1 resulted in hypersensitivity to double-strand DNA breaks (DSBs). In response to ICLs, JMJD-1.1 did not affect the focus formation of FCD-2, a homolog of FANCD2, a key protein in the Fanconi anemia pathway...
2015: PloS One
Steven Zuryn, Arnaud Ahier, Manuela Portoso, Esther Redhouse White, Marie-Charlotte Morin, Raphaël Margueron, Sophie Jarriault
Natural interconversions between distinct somatic cell types have been reported in species as diverse as jellyfish and mice. The efficiency and reproducibility of some reprogramming events represent unexploited avenues in which to probe mechanisms that ensure robust cell conversion. We report that a conserved H3K27me3/me2 demethylase, JMJD-3.1, and the H3K4 methyltransferase Set1 complex cooperate to ensure invariant transdifferentiation (Td) of postmitotic Caenorhabditis elegans hindgut cells into motor neurons...
August 15, 2014: Science
Ho-Youl Lee, Kang Choi, Hookeun Oh, Young-Kwon Park, Hyunsung Park
Jumonji domain-containing proteins (JMJD) catalyze the oxidative demethylation of a methylated lysine residue of histones by using O2, α-ketoglutarate, vitamin C, and Fe(II). Several JMJDs are induced by hypoxic stress to compensate their presumed reduction in catalytic activity under hypoxia. In this study, we showed that an H3K27me3 specific histone demethylase, JMJD3 was induced by hypoxia-inducible factor (HIF)-1α/β under hypoxia and that treatment with Clioquinol, a HIF-1α activator, increased JMJD3 expression even under normoxia...
January 2014: Molecules and Cells
Se-Young Oh, Caroline G Balch, Rachael L Cliff, Bhawani S Sharma, Herman J Boermans, H V L N Swamy, V Margaret Quinton, Niel A Karrow
In this study, the modulation of key enzymes involved in epigenetic regulation was assessed in immortalized bovine macrophages (BoMacs) following in vitro exposure to the following Penicillium mycotoxins: citrinin (CIT), ochratoxin A (OTA), patulin (PAT), mycophenolic acid (MPA), penicillic acid (PA), or a combination of one of the above with OTA at the concentration that inhibits BoMac proliferation by 25 % (IC25). Real-time PCR analysis of the genes coding DNA methyltransferases (DNMTs), histone demethylases (JMJD-3 and UTX), as well as the class-1 histone deacetylases (HDAC-1, -2, and -3) and histone acetylase (Bmi-1) was assessed following 6 h of mycotoxin exposure...
November 2013: Mycotoxin Research
J Adam, M Yang, T Soga, P J Pollard
Cancer-associated mutations have been identified in the metabolic genes succinate dehydrogenase (SDH), fumarate hydratase (FH) and isocitrate dehydrogenase (IDH), advancing and challenging our understanding of cellular function and disease mechanisms and providing direct links between dysregulated metabolism and cancer. Some striking parallels exist in the cellular consequences of the genetic mutations within this triad of cancer syndromes, including accumulation of oncometabolites and competitive inhibition of 2-oxoglutarate-dependent dioxygenases, particularly, hypoxia-inducible factor (HIF) prolyl hydroxylases, JmjC domain-containing histone demethylases (part of the JMJD family) and the ten-eleven translocation (TET) family of 5methyl cytosine (5mC) DNA hydroxylases...
May 15, 2014: Oncogene
Joshua C Black, Andrew Allen, Capucine Van Rechem, Emily Forbes, Michelle Longworth, Katrin Tschöp, Claire Rinehart, Jonathan Quiton, Ryan Walsh, Andrea Smallwood, Nicholas J Dyson, Johnathan R Whetstine
The KDM4/JMJD2 family of histone demethylases is amplified in human cancers. However, little is known about their physiologic or tumorigenic roles. We have identified a conserved and unappreciated role for the JMJD2A/KDM4A H3K9/36 tridemethylase in cell cycle progression. We demonstrate that JMJD2A protein levels are regulated in a cell cycle-dependent manner and that JMJD2A overexpression increased chromatin accessibility, S phase progression, and altered replication timing of specific genomic loci. These phenotypes depended on JMJD2A enzymatic activity...
December 10, 2010: Molecular Cell
Shohei Hamada, Takayoshi Suzuki, Koshiki Mino, Koichi Koseki, Felix Oehme, Ingo Flamme, Hiroki Ozasa, Yukihiro Itoh, Daisuke Ogasawara, Haruka Komaarashi, Aiko Kato, Hiroki Tsumoto, Hidehiko Nakagawa, Makoto Hasegawa, Ryuzo Sasaki, Tamio Mizukami, Naoki Miyata
Selective inhibitors of Jumonji domain-containing protein (JMJD) histone demethylases are candidate anticancer agents as well as potential tools for elucidating the biological functions of JMJDs. On the basis of the crystal structure of JMJD2A and a homology model of JMJD2C, we designed and prepared a series of hydroxamate analogues bearing a tertiary amine. Enzyme assays using JMJD2C, JMJD2A, and prolyl hydroxylases revealed that hydroxamate analogue 8 is a potent and selective JMJD2 inhibitor, showing 500-fold greater JMJD2C-inhibitory activity and more than 9100-fold greater JMJD2C-selectivity compared with the lead compound N-oxalylglycine 2...
August 12, 2010: Journal of Medicinal Chemistry
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