Histone Variants: Dynamic Punctuation in Transcription
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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. -
ANP32A and ANP32B Are Key Factors in the Rev Dependent CRM1 Pathway
bioRxiv preprint doi: https://doi.org/10.1101/559096; this version posted February 24, 2019. The copyright holder for this preprint (which was not certified by peer review) is the author/funder.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. 1 ANP32A and ANP32B are key factors in the Rev dependent CRM1 pathway 2 for nuclear export of HIV-1 unspliced mRNA 3 Yujie Wang1, Haili Zhang1, Lei Na 1, Cheng Du1, Zhenyu Zhang1, Yong-Hui Zheng1,2, Xiaojun Wang1* 4 1State Key Laboratory of Veterinary Biotechnology, Harbin Veterinary Research Institute, the Chinese 5 Academy of Agricultural Sciences, Harbin 150069, China 6 2Department of Microbiology and Molecular Genetics, Michigan State University, East Lansing, Michigan, 7 USA. 8 * Address correspondence to Xiaojun Wang, [email protected]. 9 10 11 12 13 14 15 16 17 18 19 20 21 1 bioRxiv preprint doi: https://doi.org/10.1101/559096; this version posted February 24, 2019. 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. 22 Abstract 23 The nuclear export receptor CRM1 is an important regulator involved in the shuttling of various cellular 24 and viral RNAs between the nucleus and the cytoplasm. HIV-1 Rev interacts with CRM1 in the late phase of 25 HIV-1 replication to promote nuclear export of unspliced and single spliced HIV-1 transcripts. However, the 26 knowledge of cellular factors that are involved in the CRM1-dependent viral RNA nuclear export remains 27 inadequate. Here, we identified that ANP32A and ANP32B mediate the export of unspliced or partially spliced 28 viral mRNA via interacting with Rev and CRM1. -
H2A Ubiquitylated Mononucleosomes Next-Generation Substrates for Deubiquitylation Enzyme (DUB) Assays
H2A Ubiquitylated Mononucleosomes Next-Generation Substrates for Deubiquitylation Enzyme (DUB) Assays Next-Generation DUB Assay Substrates are here. Get results that matter. • Enabling access to DUB targets that require nucleosome substrates in vitro • Proper substrates for DUB inhibitor development • Unmatched quality control for results you can trust Histone monoubiquitylation (ub1) acts as a critical signaling center that regulates cascades of downstream epigenetic enzymes to modify gene transcription. The physiological substrate for chromatin-targeting DUBs is the nucleosome (Nuc), the basic repeating unit of chromatin (comprised of histone proteins wrapped by DNA). Current high-throughput screening (HTS) DUB assays use unnatural modified or diubiquitin conjugates as substrates, which poorly mimic endogenous targets in vivo. In collaboration with Boston Biochem, EpiCypher is delivering ubiquitylated nucleosome substrates for drug screening and chromatin biology research. FIGURE 1 Ub Ub Schematic representation of mononucleosoms assembled from recombinant human histones Ub expressed in E. coli (two each of histones H2A, H2B, H3 and H4). H2A H2A Approximately 50% of the nucleosomes are monoubiquitylated on histone H2A lysine 118, while the other 50% are monoubiquitylated on both histone H2A lysine 118 and histone H2A lysine 119 (multi-mono- ubiquitylated). Next Generation Deubiquitylation Enzyme (DUB) Assay Substrates EpiCypher has developed recombinant mononucleosomes carrying monoubiquitylation on H2A. These ubiquitylated nucleosomes are generated enzymatically using the RING1B/BMI1 ubiquitin ligase complex. The resulting product is highly pure (>95% of nucleosomes are ubiquitylated) and consists of nucleosomes monoubiquitylated at H2A lysine 118/119 (Figure 1; the physiological target of RING1B/BMI1 in vivo). FIGURE 2 Deubiquitylation Assay Data: Mononucleosomes H2A Ubiquityl, Recombinant Human, Biotinylated (1 μg) were employed in a deubiquitylation (DUB) assay using no enzyme (Lane 1), USP5 (Lane 2) or USP16 (Lane 3) and run on an SDS PAGE gel. -
A Computational Approach for Defining a Signature of Β-Cell Golgi Stress in Diabetes Mellitus
Page 1 of 781 Diabetes A Computational Approach for Defining a Signature of β-Cell Golgi Stress in Diabetes Mellitus Robert N. Bone1,6,7, Olufunmilola Oyebamiji2, Sayali Talware2, Sharmila Selvaraj2, Preethi Krishnan3,6, Farooq Syed1,6,7, Huanmei Wu2, Carmella Evans-Molina 1,3,4,5,6,7,8* Departments of 1Pediatrics, 3Medicine, 4Anatomy, Cell Biology & Physiology, 5Biochemistry & Molecular Biology, the 6Center for Diabetes & Metabolic Diseases, and the 7Herman B. Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, IN 46202; 2Department of BioHealth Informatics, Indiana University-Purdue University Indianapolis, Indianapolis, IN, 46202; 8Roudebush VA Medical Center, Indianapolis, IN 46202. *Corresponding Author(s): Carmella Evans-Molina, MD, PhD ([email protected]) Indiana University School of Medicine, 635 Barnhill Drive, MS 2031A, Indianapolis, IN 46202, Telephone: (317) 274-4145, Fax (317) 274-4107 Running Title: Golgi Stress Response in Diabetes Word Count: 4358 Number of Figures: 6 Keywords: Golgi apparatus stress, Islets, β cell, Type 1 diabetes, Type 2 diabetes 1 Diabetes Publish Ahead of Print, published online August 20, 2020 Diabetes Page 2 of 781 ABSTRACT The Golgi apparatus (GA) is an important site of insulin processing and granule maturation, but whether GA organelle dysfunction and GA stress are present in the diabetic β-cell has not been tested. We utilized an informatics-based approach to develop a transcriptional signature of β-cell GA stress using existing RNA sequencing and microarray datasets generated using human islets from donors with diabetes and islets where type 1(T1D) and type 2 diabetes (T2D) had been modeled ex vivo. To narrow our results to GA-specific genes, we applied a filter set of 1,030 genes accepted as GA associated. -
A. Cellular Senescence
Generation of antisense RNAs at convergent gene loci in cells undergoing senescence Maharshi Krishna Deb To cite this version: Maharshi Krishna Deb. Generation of antisense RNAs at convergent gene loci in cells undergo- ing senescence. Human genetics. Université Paul Sabatier - Toulouse III, 2016. English. NNT : 2016TOU30274. tel-03209213 HAL Id: tel-03209213 https://tel.archives-ouvertes.fr/tel-03209213 Submitted on 27 Apr 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. 5)µ4& &OWVFEFMPCUFOUJPOEV %0$503"5%&-6/*7&34*5²%&506-064& %ÏMJWSÏQBS Université Toulouse 3 Paul Sabatier (UT3 Paul Sabatier) 1SÏTFOUÏFFUTPVUFOVFQBS DEB Maharshi Krishna -F mercredi 30 mars 2016 5Jtre : Generation of antisense RNAs at convergent gene loci in cells undergoing senescence École doctorale et discipline ou spécialité : ED BSB : Génétique moléculaire 6OJUÏEFSFDIFSDIF CNRS-UMR5088; LBCMCP %JSFDUFVS T EFʾÒTF Dr. TROUCHE Didier Co-Directeur/trice(s) de Thèse : Dr. NICOLAS Estelle 3BQQPSUFVST Prof. GILSON Eric, Dr. LIBRI Domenico, Dr. VERDEL Andre "VUSF T NFNCSF T EVKVSZ Prof. GLEIZES Pierre Emmanuel, President of Jury Dr. TROUCHE Didier, Thesis Supervisor This thesis is dedicated to any patients who may get cured with treatments manifesting from this work. -
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. -
Supplementary Data
SUPPLEMENTARY DATA A cyclin D1-dependent transcriptional program predicts clinical outcome in mantle cell lymphoma Santiago Demajo et al. 1 SUPPLEMENTARY DATA INDEX Supplementary Methods p. 3 Supplementary References p. 8 Supplementary Tables (S1 to S5) p. 9 Supplementary Figures (S1 to S15) p. 17 2 SUPPLEMENTARY METHODS Western blot, immunoprecipitation, and qRT-PCR Western blot (WB) analysis was performed as previously described (1), using cyclin D1 (Santa Cruz Biotechnology, sc-753, RRID:AB_2070433) and tubulin (Sigma-Aldrich, T5168, RRID:AB_477579) antibodies. Co-immunoprecipitation assays were performed as described before (2), using cyclin D1 antibody (Santa Cruz Biotechnology, sc-8396, RRID:AB_627344) or control IgG (Santa Cruz Biotechnology, sc-2025, RRID:AB_737182) followed by protein G- magnetic beads (Invitrogen) incubation and elution with Glycine 100mM pH=2.5. Co-IP experiments were performed within five weeks after cell thawing. Cyclin D1 (Santa Cruz Biotechnology, sc-753), E2F4 (Bethyl, A302-134A, RRID:AB_1720353), FOXM1 (Santa Cruz Biotechnology, sc-502, RRID:AB_631523), and CBP (Santa Cruz Biotechnology, sc-7300, RRID:AB_626817) antibodies were used for WB detection. In figure 1A and supplementary figure S2A, the same blot was probed with cyclin D1 and tubulin antibodies by cutting the membrane. In figure 2H, cyclin D1 and CBP blots correspond to the same membrane while E2F4 and FOXM1 blots correspond to an independent membrane. Image acquisition was performed with ImageQuant LAS 4000 mini (GE Healthcare). Image processing and quantification were performed with Multi Gauge software (Fujifilm). For qRT-PCR analysis, cDNA was generated from 1 µg RNA with qScript cDNA Synthesis kit (Quantabio). qRT–PCR reaction was performed using SYBR green (Roche). -
GENOME EDITING in AFRICA’S AGRICULTURE 2021 an EARLY TAKE-OFF TABLE of CONTENTS Abbreviations and Acronyms 3
GENOME EDITING IN AFRICA’S AGRICULTURE 2021 AN EARLY TAKE-OFF TABLE OF CONTENTS Abbreviations and Acronyms 3 1. Introduction 4 1.1 Milestones in Plant Breeding 5 1.2 How CRISPR genome editing works in agriculture 6 2 . Genome editing projects and experts in eastern Africa 7 2.1 Kenya 8 2.2 Ethiopia 14 2.3 Uganda 15 3 . Gene editing projects and experts in southern Africa 17 3.1 South Africa 18 4. Gene editing projects and experts in West Africa 19 4.1 Nigeria 20 5. Gene editing projects and experts in Central Africa 21 5.1 Cameroon 22 6. Gene editing projects and experts in North Africa 23 6.1 Egypt 24 7. Conclusion 25 8. CRISPR genome editing: inside a crop breeder’s toolkit 26 9. Regulatory Approaches for Genome Edited Products in Various Countries 27 10. Communicating about Genome Editing in Africa 28 2 ABBREVIATIONS AND ACRONYMS CRISPR Clustered Regularly Interspaced Short Palindromic Repeats DNA Deoxyribonucleic acid GM Genetically Modified GMO Genetically Modified Organism HDR Homology Directed Repair ISAAA International Service for the Acquisition of Agri-biotech Applications NHEJ Non Homologous End Joining PCR Polymerase Chain Reaction RNA Ribonucleic Acid LGS1 Low germination stimulant 1 3 1.0 INTRODUCTION Genome editing (also referred to as gene editing) comprises a arm is provided with the CRISPR-Cas9 cassette, homology-directed group of technologies that give scientists the ability to change an repair (HDR) will occur, otherwise the cell will employ non- organism’s DNA. These technologies allow addition, removal or homologous end joining (NHEJ) to create small indels at the cut site alteration of genetic material at particular locations in the genome. -
Identification of Differentially Methylated Cpg
biomedicines Article Identification of Differentially Methylated CpG Sites in Fibroblasts from Keloid Scars Mansour A. Alghamdi 1,2 , Hilary J. Wallace 3,4 , Phillip E. Melton 5,6 , Eric K. Moses 5,6, Andrew Stevenson 4 , Laith N. Al-Eitan 7,8 , Suzanne Rea 9, Janine M. Duke 4, 10 11 4,9,12 4, , Patricia L. Danielsen , Cecilia M. Prêle , Fiona M. Wood and Mark W. Fear * y 1 Department of Anatomy, College of Medicine, King Khalid University, Abha 61421, Saudi Arabia; [email protected] 2 Genomics and Personalized Medicine Unit, College of Medicine, King Khalid University, Abha 61421, Saudi Arabia 3 School of Medicine, The University of Notre Dame Australia, Fremantle 6959, Australia; [email protected] 4 Burn Injury Research Unit, School of Biomedical Sciences, Faculty of Health and Medical Sciences, The University of Western Australia, Perth 6009, Australia; andrew@fionawoodfoundation.com (A.S.); [email protected] (J.M.D.); fi[email protected] (F.M.W.) 5 Centre for Genetic Origins of Health and Disease, Faculty of Health and Medical Sciences, The University of Western Australia, Perth 6009, Australia; [email protected] (P.E.M.); [email protected] (E.K.M.) 6 School of Pharmacy and Biomedical Sciences, Faculty of Health Science, Curtin University, Perth 6102, Australia 7 Department of Applied Biological Sciences, Jordan University of Science and Technology, Irbid 22110, Jordan; [email protected] 8 Department of Biotechnology and Genetic Engineering, Jordan University of Science and Technology, Irbid 22110, -
ANP32B Deficiency Impairs Proliferation and Suppresses Tumor Progression by Regulating AKT Phosphorylation
Citation: Cell Death and Disease (2016) 7, e2082; doi:10.1038/cddis.2016.8 OPEN & 2016 Macmillan Publishers Limited All rights reserved 2041-4889/16 www.nature.com/cddis ANP32B deficiency impairs proliferation and suppresses tumor progression by regulating AKT phosphorylation S Yang1,6, L Zhou2,6, PT Reilly3, S-M Shen1,PHe1, X-N Zhu1, C-X Li1, L-S Wang4, TW Mak5, G-Q Chen*,1 and Y Yu*,1 The acidic leucine-rich nuclear phosphoprotein 32B (ANP32B) is reported to impact normal development, with Anp32b-knockout mice exhibiting smaller size and premature aging. However, its cellular and molecular mechanisms, especially its potential roles in tumorigenesis, remain largely unclear. Here, we utilize 'knockout' models, RNAi silencing and clinical cohorts to more closely investigate the role of this enigmatic factor in cell proliferation and cancer phenotypes. We report that, compared with Anp32b wild- type (Anp32b+/+) littermates, a broad panel of tissues in Anp32b-deficient (Anp32b− / −) mice are demonstrated hypoplasia. Anp32b− / − mouse embryo fibroblast cell has a slower proliferation, even after oncogenic immortalization. ANP32B knockdown also significantly inhibits in vitro and in vivo growth of cancer cells by inducing G1 arrest. In line with this, ANP32B protein has higher expression in malignant tissues than adjacent normal tissues from a cohort of breast cancer patients, and its expression level positively correlates with their histopathological grades. Moreover, ANP32B deficiency downregulates AKT phosphorylation, which involves its regulating effect on cell growth. Collectively, our findings suggest that ANP32B is an oncogene and a potential therapeutic target for breast cancer treatment. Cell Death and Disease (2016) 7, e2082; doi:10.1038/cddis.2016.8; published online 4 February 2016 The acidic leucine-rich nuclear phosphoprotein 32 kDa lethality and reduced body weight,22–25 indicating a greater (ANP32) protein family are characterized by a N-terminal importance of Anp32b in normal development. -
Nuclear PTEN Safeguards Pre-Mrna Splicing to Link Golgi Apparatus for Its Tumor Suppressive Role
ARTICLE DOI: 10.1038/s41467-018-04760-1 OPEN Nuclear PTEN safeguards pre-mRNA splicing to link Golgi apparatus for its tumor suppressive role Shao-Ming Shen1, Yan Ji2, Cheng Zhang1, Shuang-Shu Dong2, Shuo Yang1, Zhong Xiong1, Meng-Kai Ge1, Yun Yu1, Li Xia1, Meng Guo1, Jin-Ke Cheng3, Jun-Ling Liu1,3, Jian-Xiu Yu1,3 & Guo-Qiang Chen1 Dysregulation of pre-mRNA alternative splicing (AS) is closely associated with cancers. However, the relationships between the AS and classic oncogenes/tumor suppressors are 1234567890():,; largely unknown. Here we show that the deletion of tumor suppressor PTEN alters pre-mRNA splicing in a phosphatase-independent manner, and identify 262 PTEN-regulated AS events in 293T cells by RNA sequencing, which are associated with significant worse outcome of cancer patients. Based on these findings, we report that nuclear PTEN interacts with the splicing machinery, spliceosome, to regulate its assembly and pre-mRNA splicing. We also identify a new exon 2b in GOLGA2 transcript and the exon exclusion contributes to PTEN knockdown-induced tumorigenesis by promoting dramatic Golgi extension and secretion, and PTEN depletion significantly sensitizes cancer cells to secretion inhibitors brefeldin A and golgicide A. Our results suggest that Golgi secretion inhibitors alone or in combination with PI3K/Akt kinase inhibitors may be therapeutically useful for PTEN-deficient cancers. 1 Department of Pathophysiology, Key Laboratory of Cell Differentiation and Apoptosis of Chinese Ministry of Education, Shanghai Jiao Tong University School of Medicine (SJTU-SM), Shanghai 200025, China. 2 Institute of Health Sciences, Shanghai Institutes for Biological Sciences of Chinese Academy of Sciences and SJTU-SM, Shanghai 200025, China. -
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Published OnlineFirst February 10, 2017; DOI: 10.1158/2159-8290.CD-16-1045 RESEARCH ARTICLE Interaction Landscape of Inherited Polymorphisms with Somatic Events in Cancer Hannah Carter 1 , 2 , 3 , 4 , Rachel Marty 5 , Matan Hofree 6 , Andrew M. Gross 5 , James Jensen 5 , Kathleen M. Fisch1,2,3,7 , Xingyu Wu 2 , Christopher DeBoever 5 , Eric L. Van Nostrand 4,8 , Yan Song 4,8 , Emily Wheeler 4,8 , Jason F. Kreisberg 1,3 , Scott M. Lippman 2 , Gene W. Yeo 4,8 , J. Silvio Gutkind 2 , 3 , and Trey Ideker 1 , 2 , 3 , 4 , 5,6 Downloaded from cancerdiscovery.aacrjournals.org on September 27, 2021. © 2017 American Association for Cancer Research. Published OnlineFirst February 10, 2017; DOI: 10.1158/2159-8290.CD-16-1045 ABSTRACT Recent studies have characterized the extensive somatic alterations that arise dur- ing cancer. However, the somatic evolution of a tumor may be signifi cantly affected by inherited polymorphisms carried in the germline. Here, we analyze genomic data for 5,954 tumors to reveal and systematically validate 412 genetic interactions between germline polymorphisms and major somatic events, including tumor formation in specifi c tissues and alteration of specifi c cancer genes. Among germline–somatic interactions, we found germline variants in RBFOX1 that increased incidence of SF3B1 somatic mutation by 8-fold via functional alterations in RNA splicing. Similarly, 19p13.3 variants were associated with a 4-fold increased likelihood of somatic mutations in PTEN. In support of this associ- ation, we found that PTEN knockdown sensitizes the MTOR pathway to high expression of the 19p13.3 gene GNA11 .