Macrohistone Variants Preserve Cell Identity by Preventing the Gain of H3k4me2 During Reprogramming to Pluripotency
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Histone Variants: Deviants?
Downloaded from genesdev.cshlp.org on September 25, 2021 - Published by Cold Spring Harbor Laboratory Press REVIEW Histone variants: deviants? Rohinton T. Kamakaka2,3 and Sue Biggins1 1Division of Basic Sciences, Fred Hutchinson Cancer Research Center, Seattle, Washington 98109, USA; 2UCT/National Institutes of Health, Bethesda, Maryland 20892, USA Histones are a major component of chromatin, the pro- sealing the two turns of DNA. The nucleosome filament tein–DNA complex fundamental to genome packaging, is then folded into a 30-nm fiber mediated in part by function, and regulation. A fraction of histones are non- nucleosome–nucleosome interactions, and this fiber is allelic variants that have specific expression, localiza- probably the template for most nuclear processes. Addi- tion, and species-distribution patterns. Here we discuss tional levels of compaction enable these fibers to be recent progress in understanding how histone variants packaged into the small volume of the nucleus. lead to changes in chromatin structure and dynamics to The packaging of DNA into nucleosomes and chroma- carry out specific functions. In addition, we review his- tin positively or negatively affects all nuclear processes tone variant assembly into chromatin, the structure of in the cell. While nucleosomes have long been viewed as the variant chromatin, and post-translational modifica- stable entities, there is a large body of evidence indicat- tions that occur on the variants. ing that they are highly dynamic (for review, see Ka- makaka 2003), capable of being altered in their compo- Supplemental material is available at http://www.genesdev.org. sition, structure, and location along the DNA. Enzyme Approximately two meters of human diploid DNA are complexes that either post-translationally modify the packaged into the cell’s nucleus with a volume of ∼1000 histones or alter the position and structure of the nucleo- µm3. -
The U2AF1S34F Mutation Induces Lineage-Specific Splicing Alterations in Myelodysplastic Syndromes
RESEARCH ARTICLE The Journal of Clinical Investigation The U2AF1S34F mutation induces lineage-specific splicing alterations in myelodysplastic syndromes Bon Ham Yip,1 Violetta Steeples,1 Emmanouela Repapi,2 Richard N. Armstrong,1 Miriam Llorian,3 Swagata Roy,1 Jacqueline Shaw,1 Hamid Dolatshad,1 Stephen Taylor,2 Amit Verma,4 Matthias Bartenstein,4 Paresh Vyas,5 Nicholas C.P. Cross,6 Luca Malcovati,7 Mario Cazzola,7 Eva Hellström-Lindberg,8 Seishi Ogawa,9 Christopher W.J. Smith,3 Andrea Pellagatti,1 and Jacqueline Boultwood1 1Bloodwise Molecular Haematology Unit, Nuffield Division of Clinical Laboratory Sciences, Radcliffe Department of Medicine, University of Oxford, and BRC Blood Theme, National Institute for Health Research (NIHR) Oxford Biomedical Centre, Oxford University Hospital, Oxford, United Kingdom. 2The Computational Biology Research Group, Weatherall Institute of Molecular Medicine, University of Oxford, Oxford, United Kingdom. 3Department of Biochemistry, Downing Site, University of Cambridge, Cambridge, United Kingdom. 4Albert Einstein College of Medicine, Bronx, New York, USA. 5Medical Research Council, Molecular Hematology Unit, Weatherall Institute of Molecular Medicine, University of Oxford, and Department of Hematology, Oxford University Hospital National Health Service Trust, Oxford, United Kingdom. 6Faculty of Medicine, University of Southampton, Southampton, and National Genetics Reference Laboratory (Wessex), Salisbury, United Kingdom. 7Fondazione IRCCS Policlinico San Matteo and University of Pavia, Pavia, Italy. 8Center for Hematology and Regenerative Medicine, Karolinska University Hospital Huddinge, Stockholm, Sweden. 9Department of Pathology and Tumor Biology, Kyoto University, Kyoto, Japan. Mutations of the splicing factor–encoding gene U2AF1 are frequent in the myelodysplastic syndromes (MDS), a myeloid malignancy, and other cancers. Patients with MDS suffer from peripheral blood cytopenias, including anemia, and an increasing percentage of bone marrow myeloblasts. -
HIST1H2AK (HIST1H2AG) Human Shrna Lentiviral Particle (Locus ID 8969) Product Data
OriGene Technologies, Inc. 9620 Medical Center Drive, Ste 200 Rockville, MD 20850, US Phone: +1-888-267-4436 [email protected] EU: [email protected] CN: [email protected] Product datasheet for TL304103V HIST1H2AK (HIST1H2AG) Human shRNA Lentiviral Particle (Locus ID 8969) Product data: Product Type: shRNA Lentiviral Particles Product Name: HIST1H2AK (HIST1H2AG) Human shRNA Lentiviral Particle (Locus ID 8969) Locus ID: 8969 Synonyms: H2A.1b; H2A/p; H2AC13; H2AC15; H2AC16; H2AC17; H2AFP; H2AG; HIST1H2AG; pH2A/f Vector: pGFP-C-shLenti (TR30023) Format: Lentiviral particles RefSeq: NM_021064, NM_021064.1, NM_021064.2, NM_021064.3, NM_021064.4, BC016677, BC016677.1, BC067782, NM_021064.5 Summary: Histones are basic nuclear proteins that are responsible for the nucleosome structure of the chromosomal fiber in eukaryotes. Two molecules of each of the four core histones (H2A, H2B, H3, and H4) form an octamer, around which approximately 146 bp of DNA is wrapped in repeating units, called nucleosomes. The linker histone, H1, interacts with linker DNA between nucleosomes and functions in the compaction of chromatin into higher order structures. This gene is intronless and encodes a replication-dependent histone that is a member of the histone H2A family. Transcripts from this gene lack polyA tails but instead contain a palindromic termination element. This gene is found in the histone microcluster on chromosome 6p21.33. [provided by RefSeq, Aug 2015] shRNA Design: These shRNA constructs were designed against multiple splice variants at this gene locus. To be certain that your variant of interest is targeted, please contact [email protected]. If you need a special design or shRNA sequence, please utilize our custom shRNA service. -
The Role of Histone H2av Variant Replacement and Histone H4 Acetylation in the Establishment of Drosophila Heterochromatin
The role of histone H2Av variant replacement and histone H4 acetylation in the establishment of Drosophila heterochromatin Jyothishmathi Swaminathan, Ellen M. Baxter, and Victor G. Corces1 Department of Biology, Johns Hopkins University, Baltimore, Maryland 21218, USA Activation and repression of transcription in eukaryotes involve changes in the chromatin fiber that can be accomplished by covalent modification of the histone tails or the replacement of the canonical histones with other variants. Here we show that the histone H2A variant of Drosophila melanogaster, H2Av, localizes to the centromeric heterochromatin, and it is recruited to an ectopic heterochromatin site formed by a transgene array. His2Av behaves genetically as a PcG gene and mutations in His2Av suppress position effect variegation (PEV), suggesting that this histone variant is required for euchromatic silencing and heterochromatin formation. His2Av mutants show reduced acetylation of histone H4 at Lys 12, decreased methylation of histone H3 at Lys 9, and a reduction in HP1 recruitment to the centromeric region. H2Av accumulation or histone H4 Lys 12 acetylation is not affected by mutations in Su(var)3-9 or Su(var)2-5. The results suggest an ordered cascade of events leading to the establishment of heterochromatin and requiring the recruitment of the histone H2Av variant followed by H4 Lys 12 acetylation as necessary steps before H3 Lys 9 methylation and HP1 recruitment can take place. [Keywords: Chromatin; silencing; transcription; histone; nucleus] Received September 8, 2004; revised version accepted November 4, 2004. The basic unit of chromatin is the nucleosome, which is guchi et al. 2004). The role of histone variants, and spe- made up of 146 bp of DNA wrapped around a histone cially those of H3 and H2A, in various nuclear processes octamer composed of two molecules each of the histones has been long appreciated (Wolffe and Pruss 1996; Ah- H2A, H2B, H3, and H4. -
Genome-Wide Screen of Cell-Cycle Regulators in Normal and Tumor Cells
bioRxiv preprint doi: https://doi.org/10.1101/060350; this version posted June 23, 2016. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY-NC-ND 4.0 International license. Genome-wide screen of cell-cycle regulators in normal and tumor cells identifies a differential response to nucleosome depletion Maria Sokolova1, Mikko Turunen1, Oliver Mortusewicz3, Teemu Kivioja1, Patrick Herr3, Anna Vähärautio1, Mikael Björklund1, Minna Taipale2, Thomas Helleday3 and Jussi Taipale1,2,* 1Genome-Scale Biology Program, P.O. Box 63, FI-00014 University of Helsinki, Finland. 2Science for Life laboratory, Department of Biosciences and Nutrition, Karolinska Institutet, SE- 141 83 Stockholm, Sweden. 3Science for Life laboratory, Division of Translational Medicine and Chemical Biology, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, S-171 21 Stockholm, Sweden To identify cell cycle regulators that enable cancer cells to replicate DNA and divide in an unrestricted manner, we performed a parallel genome-wide RNAi screen in normal and cancer cell lines. In addition to many shared regulators, we found that tumor and normal cells are differentially sensitive to loss of the histone genes transcriptional regulator CASP8AP2. In cancer cells, loss of CASP8AP2 leads to a failure to synthesize sufficient amount of histones in the S-phase of the cell cycle, resulting in slowing of individual replication forks. Despite this, DNA replication fails to arrest, and tumor cells progress in an elongated S-phase that lasts several days, finally resulting in death of most of the affected cells. -
Identification of Novel Chemotherapeutic Strategies For
www.nature.com/scientificreports OPEN Identification of novel chemotherapeutic strategies for metastatic uveal melanoma Received: 17 November 2016 Paolo Fagone1, Rosario Caltabiano2, Andrea Russo3, Gabriella Lupo1, Accepted: 09 February 2017 Carmelina Daniela Anfuso1, Maria Sofia Basile1, Antonio Longo3, Ferdinando Nicoletti1, Published: 17 March 2017 Rocco De Pasquale4, Massimo Libra1 & Michele Reibaldi3 Melanoma of the uveal tract accounts for approximately 5% of all melanomas and represents the most common primary intraocular malignancy. Despite improvements in diagnosis and more effective local therapies for primary cancer, the rate of metastatic death has not changed in the past forty years. In the present study, we made use of bioinformatics to analyze the data obtained from three public available microarray datasets on uveal melanoma in an attempt to identify novel putative chemotherapeutic options for the liver metastatic disease. We have first carried out a meta-analysis of publicly available whole-genome datasets, that included data from 132 patients, comparing metastatic vs. non metastatic uveal melanomas, in order to identify the most relevant genes characterizing the spreading of tumor to the liver. Subsequently, the L1000CDS2 web-based utility was used to predict small molecules and drugs targeting the metastatic uveal melanoma gene signature. The most promising drugs were found to be Cinnarizine, an anti-histaminic drug used for motion sickness, Digitoxigenin, a precursor of cardiac glycosides, and Clofazimine, a fat-soluble iminophenazine used in leprosy. In vitro and in vivo validation studies will be needed to confirm the efficacy of these molecules for the prevention and treatment of metastatic uveal melanoma. Uveal melanoma is the most common primary intraocular cancer, and after the skin, the uveal tract is the second most common location for melanoma1. -
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 -
A Yeast Phenomic Model for the Influence of Warburg Metabolism on Genetic Buffering of Doxorubicin Sean M
Santos and Hartman Cancer & Metabolism (2019) 7:9 https://doi.org/10.1186/s40170-019-0201-3 RESEARCH Open Access A yeast phenomic model for the influence of Warburg metabolism on genetic buffering of doxorubicin Sean M. Santos and John L. Hartman IV* Abstract Background: The influence of the Warburg phenomenon on chemotherapy response is unknown. Saccharomyces cerevisiae mimics the Warburg effect, repressing respiration in the presence of adequate glucose. Yeast phenomic experiments were conducted to assess potential influences of Warburg metabolism on gene-drug interaction underlying the cellular response to doxorubicin. Homologous genes from yeast phenomic and cancer pharmacogenomics data were analyzed to infer evolutionary conservation of gene-drug interaction and predict therapeutic relevance. Methods: Cell proliferation phenotypes (CPPs) of the yeast gene knockout/knockdown library were measured by quantitative high-throughput cell array phenotyping (Q-HTCP), treating with escalating doxorubicin concentrations under conditions of respiratory or glycolytic metabolism. Doxorubicin-gene interaction was quantified by departure of CPPs observed for the doxorubicin-treated mutant strain from that expected based on an interaction model. Recursive expectation-maximization clustering (REMc) and Gene Ontology (GO)-based analyses of interactions identified functional biological modules that differentially buffer or promote doxorubicin cytotoxicity with respect to Warburg metabolism. Yeast phenomic and cancer pharmacogenomics data were integrated to predict differential gene expression causally influencing doxorubicin anti-tumor efficacy. Results: Yeast compromised for genes functioning in chromatin organization, and several other cellular processes are more resistant to doxorubicin under glycolytic conditions. Thus, the Warburg transition appears to alleviate requirements for cellular functions that buffer doxorubicin cytotoxicity in a respiratory context. -
The Landscape of Human Mutually Exclusive Splicing
bioRxiv preprint doi: https://doi.org/10.1101/133215; this version posted May 2, 2017. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY-ND 4.0 International license. The landscape of human mutually exclusive splicing Klas Hatje1,2,#,*, Ramon O. Vidal2,*, Raza-Ur Rahman2, Dominic Simm1,3, Björn Hammesfahr1,$, Orr Shomroni2, Stefan Bonn2§ & Martin Kollmar1§ 1 Group of Systems Biology of Motor Proteins, Department of NMR-based Structural Biology, Max-Planck-Institute for Biophysical Chemistry, Göttingen, Germany 2 Group of Computational Systems Biology, German Center for Neurodegenerative Diseases, Göttingen, Germany 3 Theoretical Computer Science and Algorithmic Methods, Institute of Computer Science, Georg-August-University Göttingen, Germany § Corresponding authors # Current address: Roche Pharmaceutical Research and Early Development, Pharmaceutical Sciences, Roche Innovation Center Basel, F. Hoffmann-La Roche Ltd., Basel, Switzerland $ Current address: Research and Development - Data Management (RD-DM), KWS SAAT SE, Einbeck, Germany * These authors contributed equally E-mail addresses: KH: [email protected], RV: [email protected], RR: [email protected], DS: [email protected], BH: [email protected], OS: [email protected], SB: [email protected], MK: [email protected] - 1 - bioRxiv preprint doi: https://doi.org/10.1101/133215; this version posted May 2, 2017. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. -
A Master Autoantigen-Ome Links Alternative Splicing, Female Predilection, and COVID-19 to Autoimmune Diseases
bioRxiv preprint doi: https://doi.org/10.1101/2021.07.30.454526; this version posted August 4, 2021. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY 4.0 International license. A Master Autoantigen-ome Links Alternative Splicing, Female Predilection, and COVID-19 to Autoimmune Diseases Julia Y. Wang1*, Michael W. Roehrl1, Victor B. Roehrl1, and Michael H. Roehrl2* 1 Curandis, New York, USA 2 Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, USA * Correspondence: [email protected] or [email protected] 1 bioRxiv preprint doi: https://doi.org/10.1101/2021.07.30.454526; this version posted August 4, 2021. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY 4.0 International license. Abstract Chronic and debilitating autoimmune sequelae pose a grave concern for the post-COVID-19 pandemic era. Based on our discovery that the glycosaminoglycan dermatan sulfate (DS) displays peculiar affinity to apoptotic cells and autoantigens (autoAgs) and that DS-autoAg complexes cooperatively stimulate autoreactive B1 cell responses, we compiled a database of 751 candidate autoAgs from six human cell types. At least 657 of these have been found to be affected by SARS-CoV-2 infection based on currently available multi-omic COVID data, and at least 400 are confirmed targets of autoantibodies in a wide array of autoimmune diseases and cancer. -
H2AFY Polyclonal Antibody
PRODUCT DATA SHEET Bioworld Technology,Inc. H2AFY polyclonal antibody Catalog: BS8670 Host: Rabbit Reactivity: Human,Mouse,Rat BackGround: H2AFY protein. Histones are basic nuclear proteins that are responsible DATA: for the nucleosome structure of the chromosomal fiber in eukaryotes. Nucleosomes consist of approximately 146 bp of DNA wrapped around a histone octamer composed of pairs of each of the four core histones (H2A, H2B, H3, and H4). The chromatin fiber is further compacted through the interaction of a linker histone, H1, with the DNA between the nucleosomes to form higher order chromatin structures. This gene encodes a member of the Western blot analysis of extracts of various cell lines, using H2AFY an- histone H2A family. It replaces conventional H2A his- tibody. tones in a subset of nucleosomes where it represses tran- scription and participates in stable X chromosome inacti- vation. Alternative splicing results in multiple transcript variants encoding different isoforms. Product: Rabbit IgG, 1mg/ml in PBS with 0.02% sodium azide, 50% glycerol, pH7.2 Molecular Weight: Western blot analysis of extracts of various cell lines, using H2AFY an- ~ 40kDa tibody. Swiss-Prot: O75367 Purification&Purity: The antibody was affinity-purified from rabbit antiserum by affinity-chromatography using epitope-specific im- munogen and the purity is > 95% (by SDS-PAGE). Applications: Immunofluorescence analysis of U20S cell using H2AFY antibody. WB: 1:500~1:2000 Blue: DAPI for nuclear staining. IHC: 1:50~1:200 Note: IF: 1:50~1:200 For research use only, not for use in diagnostic procedure. Storage&Stability: Store at 4°C short term. Aliquot and store at -20°C long term. -
Chew Et Al-2021-Nature Communi
Short H2A histone variants are expressed in cancer Guo-Liang Chew, Marie Bleakley, Robert Bradley, Harmit Malik, Steven Henikoff, Antoine Molaro, Jay Sarthy To cite this version: Guo-Liang Chew, Marie Bleakley, Robert Bradley, Harmit Malik, Steven Henikoff, et al.. Short H2A histone variants are expressed in cancer. Nature Communications, Nature Publishing Group, 2021, 12 (1), pp.490. 10.1038/s41467-020-20707-x. hal-03118929 HAL Id: hal-03118929 https://hal.archives-ouvertes.fr/hal-03118929 Submitted on 22 Jan 2021 HAL is a multi-disciplinary open access L’archive ouverte pluridisciplinaire HAL, est archive for the deposit and dissemination of sci- destinée au dépôt et à la diffusion de documents entific research documents, whether they are pub- scientifiques de niveau recherche, publiés ou non, lished or not. The documents may come from émanant des établissements d’enseignement et de teaching and research institutions in France or recherche français ou étrangers, des laboratoires abroad, or from public or private research centers. publics ou privés. ARTICLE https://doi.org/10.1038/s41467-020-20707-x OPEN Short H2A histone variants are expressed in cancer Guo-Liang Chew 1, Marie Bleakley2, Robert K. Bradley 3,4,5, Harmit S. Malik4,6, Steven Henikoff 4,6, ✉ ✉ Antoine Molaro 4,7 & Jay Sarthy 4 Short H2A (sH2A) histone variants are primarily expressed in the testes of placental mammals. Their incorporation into chromatin is associated with nucleosome destabilization and modulation of alternate splicing. Here, we show that sH2As innately possess features similar to recurrent oncohistone mutations associated with nucleosome instability. Through 1234567890():,; analyses of existing cancer genomics datasets, we find aberrant sH2A upregulation in a broad array of cancers, which manifest splicing patterns consistent with global nucleosome destabilization.