Histone Modifications and Their Role in Epigenetics of Atopy and Allergic Diseases
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Crystal Structure of LSD1 in Complex with 4-[5-(Piperidin-4-Ylmethoxy)-2-(P-Tolyl) Pyridin-3-Yl]Benzonitrile
molecules Article Crystal Structure of LSD1 in Complex with 4-[5-(Piperidin-4-ylmethoxy)-2-(p-tolyl) pyridin-3-yl]benzonitrile Hideaki Niwa 1 ID , Shin Sato 1, Tomoko Hashimoto 2, Kenji Matsuno 2 and Takashi Umehara 1,* ID 1 Laboratory for Epigenetics Drug Discovery, RIKEN Center for Biosystems Dynamics Research (BDR), 1-7-22 Suehiro-cho, Tsurumi, Yokohama 230-0045, Japan; [email protected] (H.N.); [email protected] (S.S.) 2 Department of Chemistry and Life Science, School of Advanced Engineering, Kogakuin University, 2665-1 Nakano, Hachioji, Tokyo 192-0015, Japan; [email protected] (T.H.); [email protected] (K.M.) * Correspondence: [email protected]; Tel.: +81-45-503-9457 Received: 28 May 2018; Accepted: 22 June 2018; Published: 26 June 2018 Abstract: Because lysine-specific demethylase 1 (LSD1) regulates the maintenance of cancer stem cell properties, small-molecule inhibitors of LSD1 are expected to be useful for the treatment of several cancers. Reversible inhibitors of LSD1 with submicromolar inhibitory potency have recently been reported, but their exact binding modes are poorly understood. In this study, we synthesized a recently reported reversible inhibitor, 4-[5-(piperidin-4-ylmethoxy)-2-(p-tolyl)pyridin-3- yl]benzonitrile, which bears a 4-piperidinylmethoxy group, a 4-methylphenyl group, and a 4-cyanophenyl group on a pyridine ring, and determined the crystal structure of LSD1 in complex with this inhibitor at 2.96 Å. We observed strong electron density for the compound, showing that its cyano group forms a hydrogen bond with Lys661, which is a critical residue in the lysine demethylation reaction located deep in the catalytic center of LSD1. -
82594016.Pdf
View metadata, citation and similar papers at core.ac.uk brought to you by CORE provided by Elsevier - Publisher Connector Structure Article Molecular Mimicry and Ligand Recognition in Binding and Catalysis by the Histone Demethylase LSD1-CoREST Complex Riccardo Baron,1,* Claudia Binda,2 Marcello Tortorici,2 J. Andrew McCammon,1 and Andrea Mattevi2,* 1Department of Chemistry and Biochemistry, Center for Theoretical Biological Physics, and Department of Pharmacology, Howard Hughes Medical Institute, University of California at San Diego, La Jolla, CA 92093-0365, USA 2Department of Genetics and Microbiology, University of Pavia, Via Ferrata 1, 27100, Pavia, Italy *Correspondence: [email protected] (R.B.), [email protected] (A.M.) DOI 10.1016/j.str.2011.01.001 SUMMARY (LSD1 or KDM1A, according to the newly adopted nomencla- ture) (Shi et al., 2004; Forneris et al., 2005). This enzyme acts Histone demethylases LSD1 and LSD2 (KDM1A/B) on mono- and dimethylated Lys4 of histone H3 through a catalyze the oxidative demethylation of Lys4 of FAD-dependent oxidative process (Figure 1A). LSD1 is often histone H3. We used molecular dynamics simula- associated to the histone deacetylases (HDAC) 1 and 2 and to tions to probe the diffusion of the oxygen substrate. the corepressor protein CoREST, which tightly binds to LSD1 Oxygen can reach the catalytic center independently enhancing both its stability and enzymatic activity. A number of from the presence of a bound histone peptide, studies have indicated that LSD1-CoREST interacts with various protein complexes involved in gene regulation and chromatin implying that LSD1 can complete subsequent deme- modification (Forneris et al., 2008; Mosammaparast and Shi, thylation cycles without detaching from the nucleo- 2010). -
Partial Deletion of Chromosome 6P Causing Developmental Delay and Mild Dysmorphisms in a Child
Vrachnis et al. Mol Cytogenet (2021) 14:39 https://doi.org/10.1186/s13039-021-00557-y CASE REPORT Open Access Partial deletion of chromosome 6p causing developmental delay and mild dysmorphisms in a child: molecular and developmental investigation and literature search Nikolaos Vrachnis1,2,3* , Ioannis Papoulidis4, Dionysios Vrachnis5, Elisavet Siomou4, Nikolaos Antonakopoulos1,2, Stavroula Oikonomou6, Dimitrios Zygouris2, Nikolaos Loukas7, Zoi Iliodromiti8, Efterpi Pavlidou9, Loretta Thomaidis6 and Emmanouil Manolakos4 Abstract Background: The interstitial 6p22.3 deletions concern rare chromosomal events afecting numerous aspects of both physical and mental development. The syndrome is characterized by partial deletion of chromosome 6, which may arise in a number of ways. Case presentation: We report a 2.8-year old boy presenting with developmental delay and mild dysmorphisms. High-resolution oligonucleotide microarray analysis revealed with high precision a 2.5 Mb interstitial 6p deletion in the 6p22.3 region which encompasses 13 genes. Conclusions: Identifcation and in-depth analysis of cases presenting with mild features of the syndrome will sharpen our understanding of the genetic spectrum of the 6p22.3 deletion. Keywords: 6p22.3 deletion, Syndrome, Developmental delay, Intellectual disability, Dysmorphism, Behavioral abnormalities, High-resolution microarray analysis Background dysmorphic features, and structural organ defects, as well Te interstitial deletion of chromosomal region 6p22.3 as intellectual disability. is a rare condition with variable phenotypic expression. We report herein a case of interstitial deletion of chro- To date, more than 30 children and adolescents with this mosome 6p investigated by array-CGH in a 2.8-year old deletion have been reported [1–11]. -
Supplementary Table S4. FGA Co-Expressed Gene List in LUAD
Supplementary Table S4. FGA co-expressed gene list in LUAD tumors Symbol R Locus Description FGG 0.919 4q28 fibrinogen gamma chain FGL1 0.635 8p22 fibrinogen-like 1 SLC7A2 0.536 8p22 solute carrier family 7 (cationic amino acid transporter, y+ system), member 2 DUSP4 0.521 8p12-p11 dual specificity phosphatase 4 HAL 0.51 12q22-q24.1histidine ammonia-lyase PDE4D 0.499 5q12 phosphodiesterase 4D, cAMP-specific FURIN 0.497 15q26.1 furin (paired basic amino acid cleaving enzyme) CPS1 0.49 2q35 carbamoyl-phosphate synthase 1, mitochondrial TESC 0.478 12q24.22 tescalcin INHA 0.465 2q35 inhibin, alpha S100P 0.461 4p16 S100 calcium binding protein P VPS37A 0.447 8p22 vacuolar protein sorting 37 homolog A (S. cerevisiae) SLC16A14 0.447 2q36.3 solute carrier family 16, member 14 PPARGC1A 0.443 4p15.1 peroxisome proliferator-activated receptor gamma, coactivator 1 alpha SIK1 0.435 21q22.3 salt-inducible kinase 1 IRS2 0.434 13q34 insulin receptor substrate 2 RND1 0.433 12q12 Rho family GTPase 1 HGD 0.433 3q13.33 homogentisate 1,2-dioxygenase PTP4A1 0.432 6q12 protein tyrosine phosphatase type IVA, member 1 C8orf4 0.428 8p11.2 chromosome 8 open reading frame 4 DDC 0.427 7p12.2 dopa decarboxylase (aromatic L-amino acid decarboxylase) TACC2 0.427 10q26 transforming, acidic coiled-coil containing protein 2 MUC13 0.422 3q21.2 mucin 13, cell surface associated C5 0.412 9q33-q34 complement component 5 NR4A2 0.412 2q22-q23 nuclear receptor subfamily 4, group A, member 2 EYS 0.411 6q12 eyes shut homolog (Drosophila) GPX2 0.406 14q24.1 glutathione peroxidase -
Histone Methylases As Novel Drug Targets. Focus on EZH2 Inhibition. Catherine BAUGE1,2,#, Céline BAZILLE 1,2,3, Nicolas GIRARD1
Histone methylases as novel drug targets. Focus on EZH2 inhibition. Catherine BAUGE1,2,#, Céline BAZILLE1,2,3, Nicolas GIRARD1,2, Eva LHUISSIER1,2, Karim BOUMEDIENE1,2 1 Normandie Univ, France 2 UNICAEN, EA4652 MILPAT, Caen, France 3 Service d’Anatomie Pathologique, CHU, Caen, France # Correspondence and copy request: Catherine Baugé, [email protected], EA4652 MILPAT, UFR de médecine, Université de Caen Basse-Normandie, CS14032 Caen cedex 5, France; tel: +33 231068218; fax: +33 231068224 1 ABSTRACT Posttranslational modifications of histones (so-called epigenetic modifications) play a major role in transcriptional control and normal development, and are tightly regulated. Disruption of their control is a frequent event in disease. Particularly, the methylation of lysine 27 on histone H3 (H3K27), induced by the methylase Enhancer of Zeste homolog 2 (EZH2), emerges as a key control of gene expression, and a major regulator of cell physiology. The identification of driver mutations in EZH2 has already led to new prognostic and therapeutic advances, and new classes of potent and specific inhibitors for EZH2 show promising results in preclinical trials. This review examines roles of histone lysine methylases and demetylases in cells, and focuses on the recent knowledge and developments about EZH2. Key-terms: epigenetic, histone methylation, EZH2, cancerology, tumors, apoptosis, cell death, inhibitor, stem cells, H3K27 2 Histone modifications and histone code Epigenetic has been defined as inheritable changes in gene expression that occur without a change in DNA sequence. Key components of epigenetic processes are DNA methylation, histone modifications and variants, non-histone chromatin proteins, small interfering RNA (siRNA) and micro RNA (miRNA). -
Official Symbol Accession Alias / Previous Symbol Official Full Name
Official Symbol Accession Alias / Previous Symbol Official Full Name Abcc3 NM_029600.3 1700019L09Rik,MRP3,RIKEN cDNA 1700019L09 gene ATP-binding cassette, sub-family C (CFTR/MRP), member 3 Abcc8 NM_011510.3 D930031B21Rik,MGD-MRK-33673,MGI:105993,MGI:3036285,RIKEN cDNA D930031B21ATP-binding gene,sulfonylurea cassette, sub-familyreceptor,Sur,SUR1 C (CFTR/MRP), member 8 Abl1 NM_009594.4 AI325092,c-Abl,E430008G22Rik,expressed sequence AI325092,MGD-MRK-1015,MGI:2138905,MGI:2443781,RIKENc-abl oncogene 1, non-receptor cDNAtyrosine E430008G22 kinase gene Adamts16 NM_172053.2 MGC:37086 a disintegrin-like and metallopeptidase (reprolysin type) with thrombospondin type 1 motif, 16 Ago4 NM_153177.3 5730550L01Rik,AI481660,argonaute 4,Eif2c4,eukaryotic translation initiation factorargonaute 2C, 4,expressed RISC catalytic sequence subunit AI481660,MGI:2140312,RIKEN 4 cDNA 5730550L01 gene Agt NM_007428.3 AI265500,angiotensin precursor,Aogen,expressed sequence AI265500,MGD-MRK-1192,MGI:2142488,Serpina8angiotensinogen (serpin peptidase inhibitor, clade A, member 8) AI464131 NM_001085515.2 AA408153,AI604836,expressed sequence AA408153,expressed sequence expressedexpressed sequence sequence AI604836,gene AI464131 model 762, (NCBI),Gm762,MGI:2140126,MGI:2140342,MGI:2685608,NET37 Ak1 NM_001198790.1 Ak-1,B430205N08Rik,MGD-MRK-1240,MGD-MRK-1244,MGI:2445070,RIKEN cDNA B430205N08adenylate kinase gene 1 Akt1 NM_001165894.1 Akt,MGD-MRK-1257,PKB,PKB/Akt,PKBalpha thymoma viral proto-oncogene 1 Akt2 NM_001110208.1 2410016A19Rik,AW554154,expressed sequence AW554154,MGD-MRK-28173,MGI:1923730,MGI:2142261,PKB,PKBbeta,RIKENthymoma -
Supplementary Materials
Supplementary materials Supplementary Table S1: MGNC compound library Ingredien Molecule Caco- Mol ID MW AlogP OB (%) BBB DL FASA- HL t Name Name 2 shengdi MOL012254 campesterol 400.8 7.63 37.58 1.34 0.98 0.7 0.21 20.2 shengdi MOL000519 coniferin 314.4 3.16 31.11 0.42 -0.2 0.3 0.27 74.6 beta- shengdi MOL000359 414.8 8.08 36.91 1.32 0.99 0.8 0.23 20.2 sitosterol pachymic shengdi MOL000289 528.9 6.54 33.63 0.1 -0.6 0.8 0 9.27 acid Poricoic acid shengdi MOL000291 484.7 5.64 30.52 -0.08 -0.9 0.8 0 8.67 B Chrysanthem shengdi MOL004492 585 8.24 38.72 0.51 -1 0.6 0.3 17.5 axanthin 20- shengdi MOL011455 Hexadecano 418.6 1.91 32.7 -0.24 -0.4 0.7 0.29 104 ylingenol huanglian MOL001454 berberine 336.4 3.45 36.86 1.24 0.57 0.8 0.19 6.57 huanglian MOL013352 Obacunone 454.6 2.68 43.29 0.01 -0.4 0.8 0.31 -13 huanglian MOL002894 berberrubine 322.4 3.2 35.74 1.07 0.17 0.7 0.24 6.46 huanglian MOL002897 epiberberine 336.4 3.45 43.09 1.17 0.4 0.8 0.19 6.1 huanglian MOL002903 (R)-Canadine 339.4 3.4 55.37 1.04 0.57 0.8 0.2 6.41 huanglian MOL002904 Berlambine 351.4 2.49 36.68 0.97 0.17 0.8 0.28 7.33 Corchorosid huanglian MOL002907 404.6 1.34 105 -0.91 -1.3 0.8 0.29 6.68 e A_qt Magnogrand huanglian MOL000622 266.4 1.18 63.71 0.02 -0.2 0.2 0.3 3.17 iolide huanglian MOL000762 Palmidin A 510.5 4.52 35.36 -0.38 -1.5 0.7 0.39 33.2 huanglian MOL000785 palmatine 352.4 3.65 64.6 1.33 0.37 0.7 0.13 2.25 huanglian MOL000098 quercetin 302.3 1.5 46.43 0.05 -0.8 0.3 0.38 14.4 huanglian MOL001458 coptisine 320.3 3.25 30.67 1.21 0.32 0.9 0.26 9.33 huanglian MOL002668 Worenine -
KDM1B Protein Full Length Mouse Recombinant Protein Expressed in Sf9 Cells
Catalog # Aliquot Size K421-30BG-20 20 µg K421-30BG-50 50 µg KDM1B Protein Full length mouse recombinant protein expressed in Sf9 cells Catalog # K421-30BG Lot # P1749-3 Product Description Purity Recombinant full-length mouse KDM1B was expressed by baculovirus in Sf9 insect cells using an N-terminal GST tag. The gene accession number is NM_172262. The purity of KDM1B was Gene Aliases determined to be >85% by densitometry. 4632428N09Rik; AI482520; Aof1 Approx. MW ~118kDa. Formulation Recombinant protein stored in 50mM Tris-HCl, pH 7.5, 150mM NaCl, 10mM glutathione, 0.1mM EDTA, 0.25mM DTT, 0.1mM PMSF, 25% glycerol. Storage and Stability Store product at –70oC. For optimal storage, aliquot target into smaller quantities after centrifugation and store at recommended temperature. For most favorable performance, avoid repeated handling and multiple freeze/thaw cycles. Scientific Background KDM1B encodes Lysine-specific histone demethylase 1B that demethylates 'Lys-4' of histone H3, a specific tag for epigenetic transcriptional activation, thereby acting as a corepressor. It specifically associates with the coding region of its target genes. Removal of endogenous KDM1B Protein KDM1B promotes an increase in H3K4me2 levels and Full length mouse recombinant protein expressed in Sf9 cells concurrent decrease in H3K9me2 levels, with a consequent down-regulation of targeted gene Catalog Number K421-30BG transcription. Lot # P1749-3 Purity >85% References Concentration 0.1 µg/µl Stability 1yr at –70oC from date of shipment o 1. Fang R, et al. Human LSD2/KDM1b/AOF1regulates gene Storage & Shipping Store product at –70 C. For optimal storage, aliquot target into smaller transcription by modulating intragenic H3K4me2 methyla- quantities after centrifugation and tion. -
Long Non-Coding RNA Landscape in Prostate Cancer Molecular Subtypes: a Feature Selection Approach
International Journal of Molecular Sciences Article Long Non-Coding RNA Landscape in Prostate Cancer Molecular Subtypes: A Feature Selection Approach Simona De Summa 1,* , Antonio Palazzo 2 , Mariapia Caputo 1, Rosa Maria Iacobazzi 3 , Brunella Pilato 1, Letizia Porcelli 3, Stefania Tommasi 1 , Angelo Virgilio Paradiso 4,† and Amalia Azzariti 3,† 1 Molecular Diagnostics and Pharmacogenetics Unit, IRCCS IstitutoTumori Giovanni Paolo II, 70124 Bari, Italy; [email protected] (M.C.); [email protected] (B.P.); [email protected] (S.T.) 2 Laboratory of Nanotechnology, IRCCS IstitutoTumori Giovanni Paolo II, 70124 Bari, Italy; [email protected] 3 Laboratory of Experimental Pharmacology, IRCCS Istituto Tumori Giovanni Paolo II, 70124 Bari, Italy; [email protected] (R.M.I.); [email protected] (L.P.); [email protected] (A.A.) 4 Scientific Directorate, IRCCS Istituto Tumori Giovanni Paolo II, 70124 Bari, Italy; [email protected] * Correspondence: [email protected] † Co-senior authors. Abstract: Prostate cancer is one of the most common malignancies in men. It is characterized by a high molecular genomic heterogeneity and, thus, molecular subtypes, that, to date, have not been used in clinical practice. In the present paper, we aimed to better stratify prostate cancer patients through the selection of robust long non-coding RNAs. To fulfill the purpose of the study, a bioinformatic approach focused on feature selection applied to a TCGA dataset was used. In such a way, LINC00668 and long non-coding(lnc)-SAYSD1-1, able to discriminate ERG/not-ERG subtypes, Citation: De Summa, S.; Palazzo, A.; were demonstrated to be positive prognostic biomarkers in ERG-positive patients. -
The BAP1 Deubiquitinase Complex Is a General Transcriptional Co-Activator
bioRxiv preprint doi: https://doi.org/10.1101/244152; this version posted January 8, 2018. The copyright holder for this preprint (which was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission. The BAP1 deubiquitinase complex is a general transcriptional co-activator Antoine Campagne1,2, Dina Zielinski1,2 ,3, Audrey Michaud1,2, Stéphanie Le Corre1,2, Florent Dingli1, Hong Chen1,2, Ivaylo Vassilev1,2 ,3, Ming-Kang Lee1,2, Nicolas Servant1,3, Damarys Loew1, Eric Pasmant4, Sophie Postel-Vinay5, Michel Wassef1,2* and Raphaël Margueron1,2* 1 Institut Curie, Paris Sciences et Lettres Research University, 75005 Paris, France. 2 INSERM U934/ CNRS UMR3215. 3 INSERM U900, Mines ParisTech. 4 EA7331, Faculty of Pharmacy, University of Paris Paris Descartes, Department of Molecular Genetics Pathology, Cochin Hospital, HUPC AP-HP, Paris, France. 5 Gustave Roussy, Département d'Innovation Thérapeutique et Essais Précoces, INSERM U981, Université Paris-Saclay, Villejuif, F-94805, France. *Corresponding Authors: Institut Curie - 26 rue d'Ulm, 75005 Paris Emails: [email protected] or [email protected] Tel: +33 (0)156246551 Fax: +33 (0)156246939 bioRxiv preprint doi: https://doi.org/10.1101/244152; this version posted January 8, 2018. The copyright holder for this preprint (which was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission. ABSTRACT In Drosophila, a complex consisting of Calypso and ASX catalyzes H2A deubiquitination and has been reported to act as part of the Polycomb machinery in transcriptional silencing. The mammalian homologs of these proteins (BAP1 and ASXL1/2/3, respectively), are frequently mutated in various cancer types, yet their precise functions remain unclear. -
Ordered Changes in Histone Modifications at the Core of The
Ordered changes in histone modifications at the core of the Arabidopsis circadian clock Jordi Malapeira1, Lucie Crhak Khaitova1, and Paloma Mas2 Molecular Genetics Department, Center for Research in Agricultural Genomics (CRAG), Consortium Consejo Superior de Investigaciones Científicas–Institut de Recerca i Tecnologia Agroalimentaries–Universitat Autònoma de Barcelona–Universitat de Barcelona, Campus Universitat Autònoma de Barcelona, 08193 Barcelona, Spain Edited* by Steve A. Kay, University of California at San Diego, La Jolla, CA, and approved November 15, 2012 (received for review October 1, 2012) Circadian clock function in Arabidopsis thaliana relies on a com- RELATED 3 (SDG2/ATXR3) was proposed to play a major role plex network of reciprocal regulations among oscillator components. in H3K4 trimethylation (H3K4me3) in Arabidopsis (16, 17). Loss Here, we demonstrate that chromatin remodeling is a prevalent of SDG2/ATXR3 function results in pleiotropic phenotypes, as well regulatory mechanism at the core of the clock. The peak-to-trough as a global decrease of H3K4me3 accumulation and altered ex- circadian oscillation is paralleled by the sequential accumulation of pression of a large number of genes. H3 acetylation (H3K56ac, K9ac), H3K4 trimethylation (H3K4me3), A precise regulation of gene expression is not only essential and H3K4me2. Inhibition of acetylation and H3K4me3 abolishes os- for plant responses to environmental stresses and developmental cillator gene expression, indicating that both marks are essential for transitions but also for proper function of the circadian clock. gene activation. Mechanistically, blocking H3K4me3 leads to in- The circadian clockwork allows plants to anticipate environ- creased clock-repressor binding, suggesting that H3K4me3 functions mental changes and adapt their activity to the most appropriate as a transition mark modulating the progression from activation to time of day (18). -
Epigenetic Regulation of Development by Histone Lysine Methylation
Heredity (2010) 105, 24–37 & 2010 Macmillan Publishers Limited All rights reserved 0018-067X/10 $32.00 www.nature.com/hdy REVIEW Epigenetic regulation of development by histone lysine methylation S Dambacher1, M Hahn1 and G Schotta Munich Center for Integrated Protein Science (CiPSM) and Adolf-Butenandt-Institute, Ludwig-Maximilians-University, Munich, Germany Epigenetic mechanisms contribute to the establishment and (HMTases) and specific binding factors for most methylated maintenance of cell-type-specific gene expression patterns. lysine positions has provided a novel insight into the mechanisms In this review, we focus on the functions of histone lysine of epigenetic gene regulation. In addition, analyses of HMTase methylation in the context of epigenetic gene regulation during knockout mice show that histone lysine methylation has developmental transitions. Over the past few years, analysis of important functions for normal development. In this study, we histone lysine methylation in active and repressive nuclear review mechanisms of gene activation and repression by histone compartments and, more recently, genome-wide profiling of lysine methylation and discuss them in the context of the histone lysine methylation in different cell types have revealed developmental roles of HMTases. correlations between particular modifications and the transcrip- Heredity (2010) 105, 24–37; doi:10.1038/hdy.2010.49; tional status of genes. Identification of histone methyltransferases published online 5 May 2010 Keywords: epigenetics; histone lysine methylation; heterochromatin; mouse development Introduction Activation and repression are facilitated by Development is accomplished by spatial and temporal histone lysine methylation regulation of gene expression patterns. The identity of Major methylation sites on histones H3 and H4 are each cell type is maintained and passed on to daughter located in the tail (H3K4, H3K9, H3K27, H3K36 and cells by mechanisms that do not alter the DNA sequence H4K20) and the nucleosome core region (H3K79).