The Role of EZH2 in the Induction and Maintenance of Acute Myeloid Leukaemia
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In Vivo Studies Using the Classical Mouse Diversity Panel
The Mouse Diversity Panel Predicts Clinical Drug Toxicity Risk Where Classical Models Fail Alison Harrill, Ph.D The Hamner-UNC Institute for Drug Safety Sciences 0 The Importance of Predicting Clinical Adverse Drug Reactions (ADR) Figure: Cath O’Driscoll Nature Publishing 2004 Risk ID PGx Testing 1 People Respond Differently to Drugs Pharmacogenetic Markers Identified by Genome-Wide Association Drug Adverse Drug Risk Allele Reaction (ADR) Abacavir Hypersensitivity HLA-B*5701 Flucloxacillin Hepatotoxicity Allopurinol Cutaneous ADR HLA-B*5801 Carbamazepine Stevens-Johnson HLA-B*1502 Syndrome Augmentin Hepatotoxicity DRB1*1501 Ximelagatran Hepatotoxicity DRB1*0701 Ticlopidine Hepatotoxicity HLA-A*3303 Average preclinical populations and human hepatocytes lack the diversity to detect incidence of adverse events that occur only in 1/10,000 people. Current Rodent Models of Risk Assessment The Challenge “At a time of extraordinary scientific progress, methods have hardly changed in several decades ([FDA] 2004)… Toxicologists face a major challenge in the twenty-first century. They need to embrace the new “omics” techniques and ensure that they are using the most appropriate animals if their discipline is to become a more effective tool in drug development.” -Dr. Michael Festing Quantitative geneticist Toxicol Pathol. 2010;38(5):681-90 Rodent Models as a Strategy for Hazard Characterization and Pharmacogenetics Genetically defined rodent models may provide ability to: 1. Improve preclinical prediction of drugs that carry a human safety risk 2. -
Mutant IDH, (R)-2-Hydroxyglutarate, and Cancer
Downloaded from genesdev.cshlp.org on October 1, 2021 - Published by Cold Spring Harbor Laboratory Press REVIEW What a difference a hydroxyl makes: mutant IDH, (R)-2-hydroxyglutarate, and cancer Julie-Aurore Losman1 and William G. Kaelin Jr.1,2,3 1Department of Medical Oncology, Dana-Farber Cancer Institute, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts 02215, USA; 2Howard Hughes Medical Institute, Chevy Chase, Maryland 20815, USA Mutations in metabolic enzymes, including isocitrate whether altered cellular metabolism is a cause of cancer dehydrogenase 1 (IDH1) and IDH2, in cancer strongly or merely an adaptive response of cancer cells in the face implicate altered metabolism in tumorigenesis. IDH1 of accelerated cell proliferation is still a topic of some and IDH2 catalyze the interconversion of isocitrate and debate. 2-oxoglutarate (2OG). 2OG is a TCA cycle intermediate The recent identification of cancer-associated muta- and an essential cofactor for many enzymes, including tions in three metabolic enzymes suggests that altered JmjC domain-containing histone demethylases, TET cellular metabolism can indeed be a cause of some 5-methylcytosine hydroxylases, and EglN prolyl-4-hydrox- cancers (Pollard et al. 2003; King et al. 2006; Raimundo ylases. Cancer-associated IDH mutations alter the enzymes et al. 2011). Two of these enzymes, fumarate hydratase such that they reduce 2OG to the structurally similar (FH) and succinate dehydrogenase (SDH), are bone fide metabolite (R)-2-hydroxyglutarate [(R)-2HG]. Here we tumor suppressors, and loss-of-function mutations in FH review what is known about the molecular mechanisms and SDH have been identified in various cancers, in- of transformation by mutant IDH and discuss their im- cluding renal cell carcinomas and paragangliomas. -
Human Transcription Factor Protein-Protein Interactions in Health and Disease
HELKA GÖÖS GÖÖS HELKA Recent Publications in this Series 45/2019 Mgbeahuruike Eunice Ego Evaluation of the Medicinal Uses and Antimicrobial Activity of Piper guineense (Schumach & Thonn) 46/2019 Suvi Koskinen AND DISEASE IN HEALTH INTERACTIONS PROTEIN-PROTEIN FACTOR HUMAN TRANSCRIPTION Near-Occlusive Atherosclerotic Carotid Artery Disease: Study with Computed Tomography Angiography 47/2019 Flavia Fontana DISSERTATIONES SCHOLAE DOCTORALIS AD SANITATEM INVESTIGANDAM Biohybrid Cloaked Nanovaccines for Cancer Immunotherapy UNIVERSITATIS HELSINKIENSIS 48/2019 Marie Mennesson Kainate Receptor Auxiliary Subunits Neto1 and Neto2 in Anxiety and Fear-Related Behaviors 49/2019 Zehua Liu Porous Silicon-Based On-Demand Nanohybrids for Biomedical Applications 50/2019 Veer Singh Marwah Strategies to Improve Standardization and Robustness of Toxicogenomics Data Analysis HELKA GÖÖS 51/2019 Iryna Hlushchenko Actin Regulation in Dendritic Spines: From Synaptic Plasticity to Animal Behavior and Human HUMAN TRANSCRIPTION FACTOR PROTEIN-PROTEIN Neurodevelopmental Disorders 52/2019 Heini Liimatta INTERACTIONS IN HEALTH AND DISEASE Efectiveness of Preventive Home Visits among Community-Dwelling Older People 53/2019 Helena Karppinen Older People´s Views Related to Their End of Life: Will-to-Live, Wellbeing and Functioning 54/2019 Jenni Laitila Elucidating Nebulin Expression and Function in Health and Disease 55/2019 Katarzyna Ciuba Regulation of Contractile Actin Structures in Non-Muscle Cells 56/2019 Sami Blom Spatial Characterisation of Prostate Cancer by Multiplex -
Gene PMID WBS Locus ABR 26603386 AASDH 26603386
Supplementary material J Med Genet Gene PMID WBS Locus ABR 26603386 AASDH 26603386 ABCA1 21304579 ABCA13 26603386 ABCA3 25501393 ABCA7 25501393 ABCC1 25501393 ABCC3 25501393 ABCG1 25501393 ABHD10 21304579 ABHD11 25501393 yes ABHD2 25501393 ABHD5 21304579 ABLIM1 21304579;26603386 ACOT12 25501393 ACSF2,CHAD 26603386 ACSL4 21304579 ACSM3 26603386 ACTA2 25501393 ACTN1 26603386 ACTN3 26603386;25501393;25501393 ACTN4 21304579 ACTR1B 21304579 ACVR2A 21304579 ACY3 19897463 ACYP1 21304579 ADA 25501393 ADAM12 21304579 ADAM19 25501393 ADAM32 26603386 ADAMTS1 25501393 ADAMTS10 25501393 ADAMTS12 26603386 ADAMTS17 26603386 ADAMTS6 21304579 ADAMTS7 25501393 ADAMTSL1 21304579 ADAMTSL4 25501393 ADAMTSL5 25501393 ADCY3 25501393 ADK 21304579 ADRBK2 25501393 AEBP1 25501393 AES 25501393 AFAP1,LOC84740 26603386 AFAP1L2 26603386 AFG3L1 21304579 AGAP1 26603386 AGAP9 21304579 Codina-Sola M, et al. J Med Genet 2019; 56:801–808. doi: 10.1136/jmedgenet-2019-106080 Supplementary material J Med Genet AGBL5 21304579 AGPAT3 19897463;25501393 AGRN 25501393 AGXT2L2 25501393 AHCY 25501393 AHDC1 26603386 AHNAK 26603386 AHRR 26603386 AIDA 25501393 AIFM2 21304579 AIG1 21304579 AIP 21304579 AK5 21304579 AKAP1 25501393 AKAP6 21304579 AKNA 21304579 AKR1E2 26603386 AKR7A2 21304579 AKR7A3 26603386 AKR7L 26603386 AKT3 21304579 ALDH18A1 25501393;25501393 ALDH1A3 21304579 ALDH1B1 21304579 ALDH6A1 21304579 ALDOC 21304579 ALG10B 26603386 ALG13 21304579 ALKBH7 25501393 ALPK2 21304579 AMPH 21304579 ANG 21304579 ANGPTL2,RALGPS1 26603386 ANGPTL6 26603386 ANK2 21304579 ANKMY1 26603386 ANKMY2 -
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. -
4-6 Weeks Old Female C57BL/6 Mice Obtained from Jackson Labs Were Used for Cell Isolation
Methods Mice: 4-6 weeks old female C57BL/6 mice obtained from Jackson labs were used for cell isolation. Female Foxp3-IRES-GFP reporter mice (1), backcrossed to B6/C57 background for 10 generations, were used for the isolation of naïve CD4 and naïve CD8 cells for the RNAseq experiments. The mice were housed in pathogen-free animal facility in the La Jolla Institute for Allergy and Immunology and were used according to protocols approved by the Institutional Animal Care and use Committee. Preparation of cells: Subsets of thymocytes were isolated by cell sorting as previously described (2), after cell surface staining using CD4 (GK1.5), CD8 (53-6.7), CD3ε (145- 2C11), CD24 (M1/69) (all from Biolegend). DP cells: CD4+CD8 int/hi; CD4 SP cells: CD4CD3 hi, CD24 int/lo; CD8 SP cells: CD8 int/hi CD4 CD3 hi, CD24 int/lo (Fig S2). Peripheral subsets were isolated after pooling spleen and lymph nodes. T cells were enriched by negative isolation using Dynabeads (Dynabeads untouched mouse T cells, 11413D, Invitrogen). After surface staining for CD4 (GK1.5), CD8 (53-6.7), CD62L (MEL-14), CD25 (PC61) and CD44 (IM7), naïve CD4+CD62L hiCD25-CD44lo and naïve CD8+CD62L hiCD25-CD44lo were obtained by sorting (BD FACS Aria). Additionally, for the RNAseq experiments, CD4 and CD8 naïve cells were isolated by sorting T cells from the Foxp3- IRES-GFP mice: CD4+CD62LhiCD25–CD44lo GFP(FOXP3)– and CD8+CD62LhiCD25– CD44lo GFP(FOXP3)– (antibodies were from Biolegend). In some cases, naïve CD4 cells were cultured in vitro under Th1 or Th2 polarizing conditions (3, 4). -
Sureselect Community Design Glasgow Cancer Panels
SureSelect Community Design Glasgow Cancer Panels Biomarkers with proven or emerging utility Genomics is a key element in precision medicine's potential to transform in predicting outcome and/or drug response/resistance - The clinical space oncology. Hybrid capture-based, targeted next-generation sequencing (NGS) represents a particularly promising technology as it enables the focused profiling of each of the many cancer-relevant loci. This approach allows for Ca rapid and cost-effective detection of most cancer-relevant genomic events, nc Cancer Core with the added advantage of FFPE tissue sample compatibility. er The Glasgow Precision Oncology Laboratory (GPOL) is a team of scientists Haem Cancer Plus with internationally recognized expertise in the technology, biology, and clinical utility of cancer genomics. Among their achievements is their detailed curation of genomic data to define the landscape of clinically and biologically significant genomic events in cancer. This includes not only a published literature review (see references 1-3), but also the International Cancer High confidence cancer genes, including those that are not currently clinically Genome Consortium (ICGC) and the Pan-Cancer Analysis of Whole Genomes actionable - The development space (PCAWG) study. Figure 1. Illustration of the GPOL cancer assay suite of panels that are commercially available as part of The GPOL has leveraged these insights to design the hybrid capture-based Agilent's Community Designs. We currently offer the SureSelect Community Design (CD) Cancer Core, Cancer SureSelect cancer NGS panels. With the SureSelect platform, the GPOL team Plus, and Cancer Haem panels. This figure illustrates the has developed a suite of affordable, fit-for-purpose cancer genomic assays relative size and content overlap of each panel. -
Mouse Population-Guided Resequencing Reveals That Variants in CD44 Contribute to Acetaminophen-Induced Liver Injury in Humans
Downloaded from genome.cshlp.org on October 2, 2021 - Published by Cold Spring Harbor Laboratory Press Letter Mouse population-guided resequencing reveals that variants in CD44 contribute to acetaminophen-induced liver injury in humans Alison H. Harrill,1,2,12 Paul B. Watkins,3,12 Stephen Su,6 Pamela K. Ross,2 David E. Harbourt,5 Ioannis M. Stylianou,7 Gary A. Boorman,8 Mark W. Russo,3 Richard S. Sackler,9 Stephen C. Harris,11 Philip C. Smith,5 Raymond Tennant,8 Molly Bogue,7 Kenneth Paigen,7 Christopher Harris,9,10 Tanupriya Contractor,9 Timothy Wiltshire,5 Ivan Rusyn,1,2,14 and David W. Threadgill1,4,13,14,15 1Curriculum in Toxicology, University of North Carolina, Chapel Hill, North Carolina 27599, USA; 2Department of Environmental Sciences and Engineering, University of North Carolina, Chapel Hill, North Carolina 27599, USA; 3Division of Gastroenterology and Hepatology, University of North Carolina, Chapel Hill, North Carolina 27599, USA; 4Department of Genetics, University of North Carolina, Chapel Hill, North Carolina 27599, USA; 5School of Pharmacy, University of North Carolina, Chapel Hill, North Carolina 27599, USA; 6Department of Mouse Genetics, Genomics Institute of the Novartis Research Foundation, San Diego, California 92121, USA; 7The Jackson Laboratory, Bar Harbor, Maine 04609, USA; 8National Institute of Environmental Health Sciences, Research Triangle Park, North Carolina 27709, USA; 9Verto Institute Research Laboratories, New Brunswick, New Jersey 08903, USA; 10Cancer Institute of New Jersey, New Brunswick, New Jersey 08903, USA; 11Purdue Pharma L.P., Stamford, Connecticut 06901, USA; 12Hamner-UNC Center for Drug Safety Sciences, The Hamner Institutes for Health Sciences, Research Triangle Park, North Carolina 27709, USA; 13Department of Genetics, North Carolina State University, Raleigh, North Carolina 27695, USA Interindividual variability in response to chemicals and drugs is a common regulatory concern. -
High Density Genome Wide Genotyping-By-Sequencing and Association
www.nature.com/scientificreports OPEN High density genome wide genotyping-by-sequencing and association identifies common and Received: 24 March 2016 Accepted: 14 July 2016 low frequency SNPs, and novel Published: 10 August 2016 candidate genes influencing cow milk traits Eveline M. Ibeagha-Awemu1, Sunday O. Peters2, Kingsley A. Akwanji3, Ikhide G. Imumorin4 & Xin Zhao3 High-throughput sequencing technologies have increased the ability to detect sequence variations for complex trait improvement. A high throughput genome wide genotyping-by-sequencing (GBS) method was used to generate 515,787 single nucleotide polymorphisms (SNPs), from which 76,355 SNPs with call rates >85% and minor allele frequency ≥1.5% were used in genome wide association study (GWAS) of 44 milk traits in 1,246 Canadian Holstein cows. GWAS was accomplished with a mixed linear model procedure implementing the additive and dominant models. A strong signal within the centromeric region of bovine chromosome 14 was associated with test day fat percentage. Several SNPs were associated with eicosapentaenoic acid, docosapentaenoic acid, arachidonic acid, CLA:9c11t and gamma linolenic acid. Most of the significant SNPs for 44 traits studied are novel and located in intergenic regions or introns of genes. Novel potential candidate genes for milk traits or mammary gland functions include ERCC6, TONSL, NPAS2, ACER3, ITGB4, GGT6, ACOX3, MECR, ADAM12, ACHE, LRRC14, FUK, NPRL3, EVL, SLCO3A1, PSMA4, FTO, ADCK5, PP1R16A and TEP1. Our study further demonstrates the utility of the GBS approach for identifying population-specific SNPs for use in improvement of complex dairy traits. Milk is an important source of nutrients in human nutrition all over the world. -
Expanding the Phenotypic Spectrum of PAX6 Mutations: from Congenital Cataracts to Nystagmus
G C A T T A C G G C A T genes Article Expanding the Phenotypic Spectrum of PAX6 Mutations: From Congenital Cataracts to Nystagmus Maria Nieves-Moreno 1,* , Susana Noval 1 , Jesus Peralta 1, María Palomares-Bralo 2 , Angela del Pozo 3 , Sixto Garcia-Miñaur 4, Fernando Santos-Simarro 4 and Elena Vallespin 5 1 Department of Ophthalmology, Hospital Universitario La Paz, 28046 Madrid, Spain; [email protected] (S.N.); [email protected] (J.P.) 2 Department of Molecular Developmental Disorders, Medical and Molecular Genetics Institue (INGEMM) IdiPaz, CIBERER, Hospital Universitario La Paz, 28046 Madrid, Spain; [email protected] 3 Department of Bioinformatics, Medical and Molecular Genetics Institue (INGEMM) IdiPaz, CIBERER, Hospital Universitario La Paz, 28046 Madrid, Spain; [email protected] 4 Department of Clinical Genetics, Medical and Molecular Genetics Institue (INGEMM) IdiPaz, CIBERER, Hospital Universitario La Paz, 28046 Madrid, Spain; [email protected] (S.G.-M.); [email protected] (F.S.-S.) 5 Department of Molecular Ophthalmology, Medical and Molecular Genetics Institue (INGEMM) IdiPaz, CIBERER, Hospital Universitario La Paz, 28046 Madrid, Spain; [email protected] * Correspondence: [email protected] Abstract: Background: Congenital aniridia is a complex ocular disorder, usually associated with severe visual impairment, generally caused by mutations on the PAX6 gene. The clinical phenotype of PAX6 mutations is highly variable, making the genotype–phenotype correlations difficult to establish. Methods: we describe the phenotype of eight patients from seven unrelated families Citation: Nieves-Moreno, M.; Noval, with confirmed mutations in PAX6, and very different clinical manifestations. -
Spatial Protein Interaction Networks of the Intrinsically Disordered Transcription Factor C(%3$
Spatial protein interaction networks of the intrinsically disordered transcription factor C(%3$ Dissertation zur Erlangung des akademischen Grades Doctor rerum naturalium (Dr. rer. nat.) im Fach Biologie/Molekularbiologie eingereicht an der Lebenswissenschaftlichen Fakultät der Humboldt-Universität zu Berlin Von Evelyn Ramberger, M.Sc. Präsidentin der Humboldt-Universität zu Berlin Prof. Dr.-Ing.Dr. Sabine Kunst Dekan der Lebenswissenschaftlichen Fakultät der Humboldt-Universität zu Berlin Prof. Dr. Bernhard Grimm Gutachter: 1. Prof. Dr. Achim Leutz 2. Prof. Dr. Matthias Selbach 3. Prof. Dr. Gunnar Dittmar Tag der mündlichen Prüfung: 12.8.2020 For T. Table of Contents Selbstständigkeitserklärung ....................................................................................1 List of Figures ............................................................................................................2 List of Tables ..............................................................................................................3 Abbreviations .............................................................................................................4 Zusammenfassung ....................................................................................................6 Summary ....................................................................................................................7 1. Introduction ............................................................................................................8 1.1. Disordered proteins -
NIH Public Access Author Manuscript Nature
NIH Public Access Author Manuscript Nature. Author manuscript; available in PMC 2013 September 21. NIH-PA Author Manuscript Published in final edited form as: Nature. 2013 March 21; 495(7441): 370–374. doi:10.1038/nature11925. Nanog-dependent function of Tet1 and Tet2 in establishment of pluripotency Yael Costa1,*, Junjun Ding2,*, Thorold W. Theunissen1,3,*, Francesco Faiola2,*, Timothy A. Hore4, Pavel V. Shliaha5, Miguel Fidalgo2, Arven Saunders2, Moyra Lawrence1,3, Sabine Dietmann1, Satyabrata Das6, Dana N. Levasseur6, Zhe Li7, Mingjiang Xu7, Wolf Reik4,8, José C.R. Silva1,3,#, and Jianlong Wang2,# 1Wellcome Trust-Medical Research Council Cambridge Stem Cell Institute, University of Cambridge, Tennis Court Road, Cambridge CB2 1QR, UK 2Department of Developmental and Regenerative Biology, Black Family Stem Cell Institute, Graduate School of Biological Sciences, Mount Sinai School of Medicine, New York, NY 10029 3 NIH-PA Author Manuscript Department of Biochemistry, University of Cambridge, Tennis Court Road, Cambridge CB2 1QR, UK 4Epigenetics Programme, The Babraham Institute, Cambridge CB22 3AT, UK 5Cambridge Centre for Proteomics, Cambridge Systems Biology Centre, University of Cambridge, Tennis Court Road, Cambridge, CB2 1QR UK 6Department of Internal Medicine, and Program in Molecular and Cellular Biology, University of Iowa, Iowa City, Iowa 52242 7Department of Pediatrics, Indiana University, Indianapolis, IN 46202 8Centre for Trophoblast Research, University of Cambridge, Cambridge CB2 3EG, UK Abstract Molecular control of the pluripotent state is thought to reside in a core circuitry of master transcription factors including the homeodomain-containing protein Nanog1–2, which plays an essential role in establishing ground state pluripotency during somatic cell reprogramming3–4. While the genomic occupancy of Nanog has been extensively investigated, comparatively little is NIH-PA Author Manuscript known about Nanog-associated proteins5 and their contribution to the Nanog-mediated reprogramming process.