DOCSLIB.ORG

Vitamin D Genes & Exposure in Relation to Kidney Cancer by Sara

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
Vitamin D Genes & Exposure in Relation to Kidney Cancer by Sara Vitamin D Genes & Exposure in Relation to Kidney Cancer by Sara Karami B.S., Biology, James Madison University, 2002 M.P.H, Epidemiology, The George Washington University, 2004 A Dissertation submitted to The Faculty of The Columbian College of Arts and Science of The George Washington University in partial fulfillment of the requirements for the degree of Doctor of Philosophy August 31, 2009 Dissertation directed by Katherine L. Hunting Professor of Environmental and Occupational Health and of Epidemiology and Biostatistics and Lee E. Moore Epidemiological Investigator, NIH, NCI The Columbian College of Arts and Science of The George Washington University certifies that Sara Karami has passed the Final Examination for the degree of Doctor of Philosophy as of August 12, 2009. This is the final and approved form of the dissertation. Vitamin D Genes & Exposure in Relation to Kidney Cancer Sara Karami Dissertation Research Committee: Katherine L. Hunting, Professor of Environmental and Occupational Health and of Epidemiology and Biostatistics, Dissertation Director Lee E. Moore, Epidemiological Investigator, NIH, NCI, Co-Director Paul H. Levine, Professor of Epidemiology and Biostatistics, Committee Member Yinglei Lai, Assistant Professor of Statistics, Committee Member ii © Copyright 2009 by Sara Karami All rights reserved iii Dedication The author wishes to thank everyone involved in the dissertation process for their guidance and support. Special thanks to Dr. Lee Moore, Dr. Katherine Hunting, Dr. Paul Levine, Dr. Yinglei Lai, Dr. Sean Cleary, and Dr. Donte Verme. iv Acknowledgement The author wishes to acknowledge the National Cancer Institute, the International Agency for Research on Cancer, and the School of Public Health and Health Services of The George Washington University for their assistance. v Abstract of Dissertation Vitamin D Genes & Exposure in Relation to Kidney Cancer Introduction : Vitamin D may have anti-carcinogenic properties that include inhibition of clonal tumor cell proliferation, induction of immune cell differentiation, and decreased angiogenesis. Within the kidney, vitamin D is metabolized to its active form. Since the incidence of renal cell carcinoma (RCC) and prevalence of vitamin D deficiency have increased over the past few decades, this study hypothesized that increased vitamin D exposure (via occupational ultraviolet exposure or dietary intake) was associated with decreased RCC risk and that genetic variations within the vitamin D pathway modified risk. Methods : Cases (N=1,097) and controls (N=1,476) in a hospital-based case-control study in Central Europe were interviewed to collect data on demographics and lifetime occupational histories. Genomic DNA was also collected from a subset of participants. Results : Significant reduction in RCC risk was observed with occupational ultraviolet exposure among male participants. No association between ultraviolet exposure and RCC risk was observed among females. Analyses stratified by latitude showed a stronger reduction in risk among males at the highest latitude study site, Russia. Analyses of eight vitamin D pathway genes revealed significant associations between RCC risk and the vitamin D receptor ( VDR ) and retinoid-X-receptor-alpha (RXRA ) genes. Across VDR , three haplotypes within two regions were associated with increased risk. Across RXRA , RCC risk was higher among participants with one particular haplotype located downstream of the coding region. Dietary analyses showed increased RCC risk with increasing intake frequency of yogurt for foods rich in calcium, while decreased risk was vi observed with eggs for foods rich in vitamin D. Additional evaluation of RXRA and VDR , revealed RXRA variants, 3 ′ of the coding sequence, modified associations between RCC risk and intake frequency of vitamin D rich foods, specifically eggs. Conversely, RXRA variants in introns 1 and 4 modified associations between calcium rich foods. Furthermore, increased RCC risk was observed with increasing occupational ultraviolet exposure among males with one specific VDR haplotype, centered on intron two. Conclusion : Results suggest that vitamin D is associated with RCC risk. Genetic variants across VDR and RXRA genes may be associated with RCC risk and may modify associations between RCC risk and vitamin D. vii Table of Contents Dedication iv Acknowledgments v Abstract of Dissertation vi Table of Contents viii List of Figures ix List of Tables x List of Symbols / Nomenclature xii Chapter 1: Cancer & Vitamin D 1 Chapter 2: Study Hypothesis, Specific Aims and the Central & Eastern 33 European Renal Cell Carcinoma (CEERCC) Study Chapter 3: Occupational Sunlight Exposure and Risk of Renal Cell Carcinoma 55 Chapter 4: Analysis of SNPs and Haplotypes in VDR Pathway Genes and Renal 81 Cancer Risk Chapter 5: Effect of VDR pathway genes on vitamin D intake and exposure 129 and Renal Cancer Risk Chapter 6: Past, Present and Future of Vitamin D and Cancer Risk Studies 157 References 186 Appendices 238 viii List of Figures Figure 1: Worldwide kidney cancer incidence rates from 1998 to 2000 2 Figure 2: U.S. incidence and mortality rates for kidney cancer from 1975 4 to 2001 Figure 3: Synthesis of vitamin D in the body from diet & sunlight exposure 9 Figure 4: Genes involved in the vitamin D pathway 29 Figure 5: Power calculations to detect an OR of 1.3-1.5 fold increase in RCC 52 risk with 900 cases and 900 controls Figure 6: Power calculations to detect an OR of 1.3-1.5 fold increase in RCC 53 risk with 1,100 cases and 1,100 controls Figure 7: HaploWalk and Haploview analysis for the group specific 250 component ( GC ) vitamin D binding protein gene Figure 8: HaploWalk and Haploview analysis for the signal transducer and 252 activator of transcription ( STAT1 ) gene ix List of Tables Table 1: Epidemiological studies of dietary exposures and RCC risk 5 Table 2: Dietary Intake for Vitamin D Recommended by the National 18 Academy of Science Table 3: Common VDR variants and risk of prostate cancer 24 Table 4: Common VDR variants and risk of breast cancer 27 Table 5: General characteristics of participants in the CEERCC study 41 Table 6: Power to detect a two-fold interaction with 900 cases and 900 controls 54 Table 7: Tissue that express VDR 169 Table 8: SEER Skin Cancer (excluding Basal and Squamous) Rates from 184 2001-2005 Table 9: Risk of renal cell carcinoma and exposure to occupational sunlight 239 by body mass index Table 10: Risk of renal cell carcinoma and exposure to occupational sunlight 240 by body mass index among male participants Table 11: Risk of renal cell carcinoma and exposure to occupational sunlight 241 by body mass index among female participants Table 12: Risk of renal cell carcinoma and exposure to occupational sunlight 243 by hypertensive status Table 13: Risk of renal cell carcinoma and exposure to occupational sunlight 244 by hypertensive status among male participants Table 14: Risk of renal cell carcinoma and exposure to occupational sunlight 245 by hypertensive status among female participants x Table 15: Risk of renal cell carcinoma and exposure to occupational sunlight 247 by dietary intake of calcium rich foods among female participants Table 16: Haplotype associations with genes in the vitamin D pathway 251 Table 17: Gene-gene analyses for vitamin D pathway genes and RCC risk 254 Table 18: Joint effect of vitamin D pathway genes and dietary intake 256 frequency of total vitamin D on renal cancer risk Table 19: Joint effect of vitamin D pathway genes and dietary intake 258 frequency of total calcium on renal cancer risk Table 20: Joint effect of vitamin D pathway genes and cumulative 260 occupational UV exposure on renal cancer risk Table 21: Population attributable risk among participants occupationally 263 exposed to sunlight Table 22: Population attributable risk for dietary intake frequency of total 264 vitamin D Table23: Population attributable risk among VDR genotyped participants 265 xi List of Symbols / Nomenclature 1. 1,25(OH) 2D: 1,25 dihydroxycholecalciferol or calcitriol 2. 1,25(OH) 2: 1,25-dihydroxy 3. 19-nor-1,25-dihydroxyvitamin D 2: paricacitol 4. 25(OH): 25-hydroxy 5. 7DHC: 7-dehydrocholesterol 6. 95% CI: 95% confidence interval 7. AIPC: androgen-independent prostate cancer 8. BMI: body mass index 9. CEERCC: Central & Eastern European Renal Cell Carcinoma 10. CGF: Core Genotyping Facility 11. CYP24A1 : cytochrome P450, family 24, subfamily A, polypeptide 1 or 24- dehydroxylase 12. DNA: deoxyribonucleic acid 13. DRIP : vitamin D receptor interacting protein 14. FDR: false discovery rate 15. GC : group specific component 16. HCC: hepatocellular carcinoma 17. IARC: International Agency for Research on Cancer 18. ICD-O: International Classification of Diseases for Oncology 19. ISCO: International Standard Classification of Occupation 20. IU: International Units 21. JEM: job exposure matrix xii 22. LD: linkage disequilibrium 23. MAF: minor allele frequency 24. Min-P: minimum-p-value permutation 25. mRNA: messenger ribonucleic acid 26. NACE: Statistical Classification of Economic Activities of the European Community 27. NCI: National Cancer Institute 28. NHANES: National Health and Nutrition Examination Survey 29. NHL: non-Hodgkin lymphoma 30. OPA: Oligo Pool All 31. OR: odds ratio 32. PAR: Population Attributable Risk 33. PCR: polymerase chain reaction 34. PSA: prostate specific antigen 35. PTH: parathyroid hormone 36. RCC: renal cell carcinoma 37. RFLP: restriction-fragment length polymorphism 38. RR: relative risk 39. RXR :
Load more

Recommended publications
  • 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.
    [Show full text]
  • RING1 Antibody (N-Term) Affinity Purified Rabbit Polyclonal Antibody (Pab) Catalog # AP14560A
    10320 Camino Santa Fe, Suite G San Diego, CA 92121 Tel: 858.875.1900 Fax: 858.622.0609 RING1 Antibody (N-term) Affinity Purified Rabbit Polyclonal Antibody (Pab) Catalog # AP14560A Specification RING1 Antibody (N-term) - Product Information Application WB,E Primary Accession Q06587 Other Accession Q6MGB6, O35730, NP_002922.2 Reactivity Human Predicted Mouse, Rat Host Rabbit Clonality Polyclonal Isotype Rabbit Ig Antigen Region 95-123 RING1 Antibody (N-term) - Additional Information RING1 Antibody (N-term) (Cat. #AP14560a) Gene ID 6015 western blot analysis in MDA-MB453 cell line lysates (35ug/lane).This demonstrates the Other Names RING1 antibody detected the RING1 protein E3 ubiquitin-protein ligase RING1, 632-, (arrow). Polycomb complex protein RING1, RING finger protein 1, Really interesting new gene 1 protein, RING1, RNF1 RING1 Antibody (N-term) - Background Target/Specificity This gene belongs to the RING finger family, This RING1 antibody is generated from members of rabbits immunized with a KLH conjugated synthetic peptide between 95-123 amino which encode proteins characterized by a RING acids from the N-terminal region of human domain, a RING1. zinc-binding motif related to the zinc finger domain. The gene Dilution product can bind DNA and can act as a WB~~1:1000 transcriptional repressor. It is associated with the multimeric polycomb Format group protein complex. Purified polyclonal antibody supplied in PBS The gene product interacts with the polycomb with 0.09% (W/V) sodium azide. This group proteins BMI1, antibody is purified through a protein A EDR1, and CBX4, and colocalizes with these column, followed by peptide affinity proteins in large purification.
    [Show full text]
  • Genome-Wide DNA Methylation Analysis of KRAS Mutant Cell Lines Ben Yi Tew1,5, Joel K
    www.nature.com/scientificreports OPEN Genome-wide DNA methylation analysis of KRAS mutant cell lines Ben Yi Tew1,5, Joel K. Durand2,5, Kirsten L. Bryant2, Tikvah K. Hayes2, Sen Peng3, Nhan L. Tran4, Gerald C. Gooden1, David N. Buckley1, Channing J. Der2, Albert S. Baldwin2 ✉ & Bodour Salhia1 ✉ Oncogenic RAS mutations are associated with DNA methylation changes that alter gene expression to drive cancer. Recent studies suggest that DNA methylation changes may be stochastic in nature, while other groups propose distinct signaling pathways responsible for aberrant methylation. Better understanding of DNA methylation events associated with oncogenic KRAS expression could enhance therapeutic approaches. Here we analyzed the basal CpG methylation of 11 KRAS-mutant and dependent pancreatic cancer cell lines and observed strikingly similar methylation patterns. KRAS knockdown resulted in unique methylation changes with limited overlap between each cell line. In KRAS-mutant Pa16C pancreatic cancer cells, while KRAS knockdown resulted in over 8,000 diferentially methylated (DM) CpGs, treatment with the ERK1/2-selective inhibitor SCH772984 showed less than 40 DM CpGs, suggesting that ERK is not a broadly active driver of KRAS-associated DNA methylation. KRAS G12V overexpression in an isogenic lung model reveals >50,600 DM CpGs compared to non-transformed controls. In lung and pancreatic cells, gene ontology analyses of DM promoters show an enrichment for genes involved in diferentiation and development. Taken all together, KRAS-mediated DNA methylation are stochastic and independent of canonical downstream efector signaling. These epigenetically altered genes associated with KRAS expression could represent potential therapeutic targets in KRAS-driven cancer. Activating KRAS mutations can be found in nearly 25 percent of all cancers1.
    [Show full text]
  • RING1 Proteins Contribute to Early Proximal-Distal Specification of The
    © 2016. Published by The Company of Biologists Ltd | Development (2016) 143, 276-285 doi:10.1242/dev.127506 RESEARCH ARTICLE RING1 proteins contribute to early proximal-distal specification of the forelimb bud by restricting Meis2 expression Nayuta Yakushiji-Kaminatsui1,*,‡, Takashi Kondo1,2,3, Takaho A. Endo4, Yoko Koseki1,2, Kaori Kondo1,2,3, Osamu Ohara4, Miguel Vidal5 and Haruhiko Koseki1,2,‡ ABSTRACT subunits to catalyze histone H2A monoubiquitylation at lysine 119 Polycomb group (PcG) proteins play a pivotal role in silencing (H2AK119ub1). PRC1 also targets chromatin compaction by SAM developmental genes and help to maintain various stem and domain polymerization of PHC1 and PHC2, a mammalian PH precursor cells and regulate their differentiation. PcG factors also ortholog, via H3K27me3 recognition by chromodomain proteins regulate dynamic and complex regional specification, particularly in such as CBX7 and CBX2 (Cao et al., 2002; Endoh et al., 2012; mammals, but this activity is mechanistically not well understood. In Isono et al., 2013; Kuzmichev et al., 2002). Recent studies identified this study, we focused on proximal-distal (PD) patterning of the a variant PRC1 complex containing RYBP (Ring1 and YY1 mouse forelimb bud to elucidate how PcG factors contribute to a binding protein)/YAF (YY1-associated factor), RING1A/B and a regional specification process that depends on developmental distinct PCGF subunit (Gao et al., 2012; Tavares et al., 2012), and signals. Depletion of the RING1 proteins RING1A (RING1) and demonstrated that H2AK119ub1 mediated by this variant PRC1 RING1B (RNF2), which are essential components of Polycomb leads to the recruitment of PRC2 and placement of H3K27me3 to repressive complex 1 (PRC1), led to severe defects in forelimb initiate Polycomb repression (Blackledge et al., 2014).
    [Show full text]
  • Structural and Spatial Chromatin Features at Developmental Gene Loci in Human Pluripotent Stem Cells
    ARTICLE DOI: 10.1038/s41467-017-01679-x OPEN Structural and spatial chromatin features at developmental gene loci in human pluripotent stem cells Hiroki Ikeda1, Masamitsu Sone1,2, Shinya Yamanaka1,3 & Takuya Yamamoto 1,2,4 Higher-order chromatin organization controls transcriptional programs that govern cell properties and functions. In order for pluripotent stem cells (PSCs) to appropriately respond 1234567890 to differentiation signals, developmental gene loci should be structurally and spatially regu- lated to be readily available for immediate transcription, even though these genes are hardly expressed in PSCs. Here, we show that both chromatin interaction profiles and nuclear positions at developmental gene loci differ between human somatic cells and hPSCs, and that changes in the chromatin interactions are closely related to the nuclear repositioning. Moreover, we also demonstrate that developmental gene loci, which have bivalent histone modifications, tend to colocalize in PSCs. Furthermore, this colocalization requires PRC1, PRC2, and TrxG complexes, which are essential regulatory factors for the maintenance of transcriptionally poised developmental genes. Our results indicate that higher-order chro- matin regulation may be an integral part of the differentiation capacity that defines pluripotency. 1 Department of Life Science Frontiers, Center for iPS Cell Research and Application (CiRA), Kyoto University, Sakyo-ku, Kyoto 606-8507, Japan. 2 Institute for Integrated Cell-Material Sciences (WPI-iCeMS), Kyoto University, Sakyo-ku, Kyoto 606-8507, Japan. 3 Gladstone Institute of Cardiovascular Disease, San Francisco, CA 94158, USA. 4 AMED-CREST, AMED 1-7-1 Otemach, Chiyodaku, Tokyo 100-0004, Japan. Correspondence and requests for materials should be addressed to T.Y.
    [Show full text]
  • Table S1. Identified Proteins with Exclusive Expression in Cerebellum of Rats of Control, 10Mg F/L and 50Mg F/L Groups
    Table S1. Identified proteins with exclusive expression in cerebellum of rats of control, 10mg F/L and 50mg F/L groups. Accession PLGS Protein Name Group IDa Score Q3TXS7 26S proteasome non-ATPase regulatory subunit 1 435 Control Q9CQX8 28S ribosomal protein S36_ mitochondrial 197 Control P52760 2-iminobutanoate/2-iminopropanoate deaminase 315 Control Q60597 2-oxoglutarate dehydrogenase_ mitochondrial 67 Control P24815 3 beta-hydroxysteroid dehydrogenase/Delta 5-->4-isomerase type 1 84 Control Q99L13 3-hydroxyisobutyrate dehydrogenase_ mitochondrial 114 Control P61922 4-aminobutyrate aminotransferase_ mitochondrial 470 Control P10852 4F2 cell-surface antigen heavy chain 220 Control Q8K010 5-oxoprolinase 197 Control P47955 60S acidic ribosomal protein P1 190 Control P70266 6-phosphofructo-2-kinase/fructose-2_6-bisphosphatase 1 113 Control Q8QZT1 Acetyl-CoA acetyltransferase_ mitochondrial 402 Control Q9R0Y5 Adenylate kinase isoenzyme 1 623 Control Q80TS3 Adhesion G protein-coupled receptor L3 59 Control B7ZCC9 Adhesion G-protein coupled receptor G4 139 Control Q6P5E6 ADP-ribosylation factor-binding protein GGA2 45 Control E9Q394 A-kinase anchor protein 13 60 Control Q80Y20 Alkylated DNA repair protein alkB homolog 8 111 Control P07758 Alpha-1-antitrypsin 1-1 78 Control P22599 Alpha-1-antitrypsin 1-2 78 Control Q00896 Alpha-1-antitrypsin 1-3 78 Control Q00897 Alpha-1-antitrypsin 1-4 78 Control P57780 Alpha-actinin-4 58 Control Q9QYC0 Alpha-adducin 270 Control Q9DB05 Alpha-soluble NSF attachment protein 156 Control Q6PAM1 Alpha-taxilin 161
    [Show full text]
  • The Arabidopsis PRC1-Like Ring-Finger Proteins Are Necessary for Repression of Embryonic Traits During Vegetative Growth
    npg AtRING1/AtBMI1 are crucial for embryonic trait repression Cell Research (2010) 20:1332-1344. 1332 © 2010 IBCB, SIBS, CAS All rights reserved 1001-0602/10 $ 32.00 npg ORIGINAL ARTICLE www.nature.com/cr The Arabidopsis PRC1-like ring-finger proteins are necessary for repression of embryonic traits during vegetative growth Donghong Chen1, Anne Molitor1, Chunlin Liu2, Wen-Hui Shen1 1Institut de Biologie Moléculaire des Plantes du CNRS, Université de Strasbourg, 12 rue du Général Zimmer, 67084 Strasbourg Cedex, France; 2Hunan Provincial Key Laboratory of Crop Germplasm Innovation and Utilization, Hunan Agricultural University, Changsha 410128, China Polycomb group genes play crucial roles in the maintenance of the transcriptionally silenced state of genes for proper cell differentiation in animals and plants. While components of the polycomb repressive complex2 (PRC2) are evolutionarily conserved and their functions are extensively studied in plants, PRC1 differs considerably between animals and plants, and its functions in plants are as yet not well described. Previous studies have identified the Arabidopsis AtRING1a and AtRING1b as homologues of the animal PRC1 subunit RING1. Here, we show that the Atring1a Atring1b double mutant exhibits derepression of embryonic traits during vegetative growth. Accordingly, several key regulatory genes involved in embryogenesis and stem cell activity are ectopically expressed in the mutant. Furthermore, we show that the mutant phenotypes and increased expression of regulatory genes are enhanced by the PRC2 mutant clf. Finally, we show that three homologues of the animal PRC1-subunit ring-finger protein BMI1, AtBMI1a, AtBMI1b and AtBMI1c, can bind with AtRING1a or AtRING1b, and in addition, AtBMI1c can bind with LHP1.
    [Show full text]
  • Figure S1. HAEC ROS Production and ML090 NOX5-Inhibition
    Figure S1. HAEC ROS production and ML090 NOX5-inhibition. (a) Extracellular H2O2 production in HAEC treated with ML090 at different concentrations and 24 h after being infected with GFP and NOX5-β adenoviruses (MOI 100). **p< 0.01, and ****p< 0.0001 vs control NOX5-β-infected cells (ML090, 0 nM). Results expressed as mean ± SEM. Fold increase vs GFP-infected cells with 0 nM of ML090. n= 6. (b) NOX5-β overexpression and DHE oxidation in HAEC. Representative images from three experiments are shown. Intracellular superoxide anion production of HAEC 24 h after infection with GFP and NOX5-β adenoviruses at different MOIs treated or not with ML090 (10 nM). MOI: Multiplicity of infection. Figure S2. Ontology analysis of HAEC infected with NOX5-β. Ontology analysis shows that the response to unfolded protein is the most relevant. Figure S3. UPR mRNA expression in heart of infarcted transgenic mice. n= 12-13. Results expressed as mean ± SEM. Table S1: Altered gene expression due to NOX5-β expression at 12 h (bold, highlighted in yellow). N12hvsG12h N18hvsG18h N24hvsG24h GeneName GeneDescription TranscriptID logFC p-value logFC p-value logFC p-value family with sequence similarity NM_052966 1.45 1.20E-17 2.44 3.27E-19 2.96 6.24E-21 FAM129A 129. member A DnaJ (Hsp40) homolog. NM_001130182 2.19 9.83E-20 2.94 2.90E-19 3.01 1.68E-19 DNAJA4 subfamily A. member 4 phorbol-12-myristate-13-acetate- NM_021127 0.93 1.84E-12 2.41 1.32E-17 2.69 1.43E-18 PMAIP1 induced protein 1 E2F7 E2F transcription factor 7 NM_203394 0.71 8.35E-11 2.20 2.21E-17 2.48 1.84E-18 DnaJ (Hsp40) homolog.
    [Show full text]
  • Are the Immunomodulatory Properties of Vitamin D Dependent Upon Route of Supplementation?
    Are the Immunomodulatory Properties of Vitamin D Dependent Upon Route of Supplementation? Catherine Hawrylowicz Kylie Morgan, Antony Young Vitamin D & human health Vitamin D insufficiency is a worldwide epidemic (>1 billion affected) Vitamin D insufficiency correlates with immune disease presentation & severity • Autoimmune: IBS, RA, MS • Respiratory: Asthma, Allergy, COPD Bacterial & viral infections Low UVR exposure gradient effect • Multiple sclerosis, Type 1 diabetes • Peanut allergy in Australia Holick M, 2007. NEJM; Morgan K et al, 2017. Photochem Photobiol Sci ttp://www.australianallergycentre.com.au/wp-content/uploads/2015/09/australia-peanut-allergy.png Systematic reviews & meta-analyses of individual participant data support vitamin D supplementation Joliffe DA et al, 2017. Lancet Respir Med 5(11):881-890. Vitamin D supplementation reduced the rate of asthma exacerbations requiring treatment with systemic corticosteroids overall…….. Martineau AR et al, 2017 BMJ 356:i6583 Vitamin D supplementation was safe, protected against acute respiratory tract infection overall; greatest in very vitamin D deficient subjects when given daily/weekly; not bolus Immunological mechanisms underpinning associations of vitamin D with respiratory health i. Effective clearance of pathogens ➢Vitamin D enhances multiple antimicrobial mechanisms e.g. cathelicidin, beta-defensins, autophagy J Adams, M Hewison, J White & others ii. Controlled inflammation ➢Vitamin D enhances multiple immune regulatory/anti inflammatory pathways iii. Enhanced clinical &
    [Show full text]
  • Cpg Islands and the Regulation of Transcription
    Downloaded from genesdev.cshlp.org on September 24, 2021 - Published by Cold Spring Harbor Laboratory Press REVIEW CpG islands and the regulation of transcription Aime´e M. Deaton and Adrian Bird1 The Wellcome Trust Centre for Cell Biology, University of Edinburgh, Edinburgh EH9 3JR, United Kingdom Vertebrate CpG islands (CGIs) are short interspersed DNA In spite of their link with transcription, the functional sequences that deviate significantly from the average significance of CGIs is only just beginning to emerge. CGI genomic pattern by being GC-rich, CpG-rich, and pre- promoters turn out to have distinctive patterns of tran- dominantly nonmethylated. Most, perhaps all, CGIs are scription initiation and chromatin configuration. Their sites of transcription initiation, including thousands that regulation involves proteins (some of which specifically are remote from currently annotated promoters. Shared bind nonmethylated CpG) that influence the modifica- DNA sequence features adapt CGIs for promoter function tion status of CGI chromatin. In addition, the CpG moieties by destabilizing nucleosomes and attracting proteins that themselves are sometimes subject to cytosine methylation, create a transcriptionally permissive chromatin state. which correlates with stable shutdown of the associated Silencing of CGI promoters is achieved through dense promoter. Here we examine the properties shared by ver- CpG methylation or polycomb recruitment, again using tebrate CGIs and how transcription is regulated at these their distinctive DNA sequence composition. CGIs are sites. Recent related reviews include Illingworth and Bird therefore generically equipped to influence local chroma- (2009), Mohn and Schubeler (2009), and Blackledge and tin structure and simplify regulation of gene activity. Klose (2011). Vertebrate genomes are methylated predominantly at the Evolutionary conservation of CGIs dinucleotide CpG, and consequently are CpG-deficient owing to the mutagenic properties of methylcytosine CGIs are distinct in vertebrates due to their lack of DNA (Coulondre et al.
    [Show full text]
  • Interaction Proteomics Identifies Estrogen Receptor Beta
    Mol Cell Proteomics Papers in Press. Published on December 2, 2019 as Manuscript RA119.001817 Interaction proteomics identifies estrogen receptor beta association with multiple chromatin repressive complexes to inhibit cholesterol biosynthesis and exert an oncosuppressive role in triple-negative breast cancer Elena Alexandrova1,2*, Giorgio Giurato1,2*, Pasquale Saggese1,3, Giovanni Pecoraro1, Jessica Lamberti1, Maria Ravo1,2, Francesca Rizzo1, Domenico Rocco1, Roberta Tarallo1, Tuula A. Nyman4, Francesca Collina5, Monica Cantile5, Maurizio Di Bonito5, Gerardo Botti6, Giovanni Downloaded from Nassa1‡ and Alessandro Weisz1‡ 1 Laboratory of Molecular Medicine and Genomics, Department of Medicine, Surgery and https://www.mcponline.org Dentistry ‘Scuola Medica Salernitana’, University of Salerno, Baronissi (SA), 84081, Italy 2Genomix4Life Srl, Spin-Off of the Laboratory of Molecular Medicine and Genomics, Department of Medicine, Surgery and Dentistry ‘Scuola Medica Salernitana’, University of Salerno, Baronissi (SA), 84081, Italy at UNIVERSITETET I OSLO on January 28, 2020 3Division of Pulmonary and Critical Care Medicine, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles (CA), 90095, USA. 4Department of Immunology, Institute of Clinical Medicine, University of Oslo and Rikshospitalet Oslo, 0424 Oslo, Norway 5Pathology Unit, Istituto Nazionale Tumori-IRCCS-Fondazione G. Pascale, Naples (NA), 80131 Italy 6Scientific Direction, Istituto Nazionale Tumori-IRCCS-Fondazione G. Pascale, Naples (NA), 80131, Italy *
    [Show full text]
  • Viral Driven Epigenetic Events Alter the Expression of Cancer-Related
    www.nature.com/scientificreports OPEN Viral driven epigenetic events alter the expression of cancer- related genes in Epstein-Barr- Received: 6 March 2017 Accepted: 7 June 2017 virus naturally infected Burkitt Published: xx xx xxxx lymphoma cell lines Hector Hernandez-Vargas1, Henri Gruffat2,3,4,5,6, Marie Pierre Cros1, Audrey Diederichs1, Cécilia Sirand1, Romina C. Vargas-Ayala1, Antonin Jay1, GeoffroyD urand1, Florence Le Calvez-Kelm1, Zdenko Herceg1, Evelyne Manet2,3,4,5,6, Christopher P. Wild1, Massimo Tommasino1 & Rosita Accardi1 Epstein-Barr virus (EBV) was identified as the first human virus to be associated with a human malignancy, Burkitt’s lymphoma (BL), a pediatric cancer endemic in sub-Saharan Africa. The exact mechanism of how EBV contributes to the process of lymphomagenesis is not fully understood. Recent studies have highlighted a genetic difference between endemic (EBV+) and sporadic (EBV−) BL, with the endemic variant showing a lower somatic mutation load, which suggests the involvement of an alternative virally-driven process of transformation in the pathogenesis of endemic BL. We tested the hypothesis that a global change in DNA methylation may be induced by infection with EBV, possibly thereby accounting for the lower mutation load observed in endemic BL. Our comparative analysis of the methylation profiles of a panel of BL derived cell lines, naturally infected or not with EBV, revealed that the presence of the virus is associated with a specific pattern of DNA methylation resulting in altered expression of cellular genes with a known or potential role in lymphomagenesis. These included ID3, a gene often found to be mutated in sporadic BL.
    [Show full text]