DOCSLIB.ORG

Pathobiological Pseudohypoxia As a Putative Mechanism Underlying Myelodysplastic Syndromes

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
Pathobiological Pseudohypoxia As a Putative Mechanism Underlying Myelodysplastic Syndromes Published OnlineFirst August 23, 2018; DOI: 10.1158/2159-8290.CD-17-1203 RESEARCH ARTICLE Pathobiological Pseudohypoxia as a Putative Mechanism Underlying Myelodysplastic Syndromes Yoshihiro Hayashi 1 , Yue Zhang 2 , Asumi Yokota 1 , Xiaomei Yan 1 , Jinqin Liu 2 , Kwangmin Choi 1 , Bing Li 2 , Goro Sashida3 , Yanyan Peng 4 , Zefeng Xu 2 , Rui Huang 1 , Lulu Zhang 1 , George M. Freudiger 1 , Jingya Wang 2 , Yunzhu Dong1 , Yile Zhou 1 , Jieyu Wang 1 , Lingyun Wu 1 , 5 , Jiachen Bu 1 , 6 , Aili Chen 6 , Xinghui Zhao 1 , Xiujuan Sun 2 , Kashish Chetal7 , Andre Olsson 8 , Miki Watanabe 1 , Lindsey E. Romick-Rosendale 1 , Hironori Harada 9 , Lee-Yung Shih10 , William Tse 11 , James P. Bridges 12 , Michael A. Caligiuri 13 , Taosheng Huang 4 , Yi Zheng1 , David P. Witte 1 , Qian-fei Wang 6 , Cheng-Kui Qu 14 , Nathan Salomonis 7 , H. Leighton Grimes 1 , 8 , Stephen D. Nimer15 , Zhijian Xiao 2 , and Gang Huang 1 , 2 ABSTRACT Myelodysplastic syndromes (MDS) are heterogeneous hematopoietic disorders that are incurable with conventional therapy. Their incidence is increasing with global population aging. Although many genetic, epigenetic, splicing, and metabolic aberrations have been identifi ed in patients with MDS, their clinical features are quite similar. Here, we show that hypoxia-independent activation of hypoxia-inducible factor 1α (HIF1A) signaling is both necessary and suffi cient to induce dysplastic and cytopenic MDS phenotypes. The HIF1A transcriptional signature is generally activated in MDS patient bone marrow stem/progenitors. Major MDS-associated mutations (Dnmt3a, Tet2, Asxl1, Runx1, and Mll1 ) activate the HIF1A signature. Although inducible activation of HIF1A signaling in hematopoietic cells is suffi cient to induce MDS phenotypes, both genetic and chemi- cal inhibition of HIF1A signaling rescues MDS phenotypes in a mouse model of MDS. These fi ndings reveal HIF1A as a central pathobiologic mediator of MDS and as an effective therapeutic target for a broad spectrum of patients with MDS. SIGNIFICANCE: We showed that dysregulation of HIF1A signaling could generate the clinically relevant diversity of MDS phenotypes by functioning as a signaling funnel for MDS driver mutations. This could resolve the disconnection between genotypes and phenotypes and provide a new clue as to how a vari- ety of driver mutations cause common MDS phenotypes. Cancer Discov; 8(11); 1438–57. ©2018 AACR. See related commentary by Chen and Steidl, p. 1355. 13 1 Divisions of Pathology and Experimental Hematology and Cancer Biol- Ohio. The Ohio State University Comprehensive Cancer Center, Columbus, 14 ogy, Cincinnati Children’s Hospital Medical Center, Cincinnati, Ohio. 2 State Ohio. Division of Hematology/Oncology, Afl ac Cancer and Blood Disorders 15 Key Laboratory of Experimental Hematology, Institute of Hematology Center, Emory University School of Medicine, Atlanta, Georgia. Sylvester and Blood Diseases Hospital, Chinese Academy of Medical Sciences and Comprehensive Cancer Center, University of Miami, Miami, Florida. Peking Union Medical College, Tianjin, China. 3 International Research Note: Supplementary data for this article are available at Cancer Discovery Center for Medical Sciences, Kumamoto University, Chuo-ku, Kumamoto, Online (http://cancerdiscovery.aacrjournals.org/). Japan. 4 Division of Human Genetics, Cincinnati Children’s Hospital Medi- Current address for Y. Hayashi: Laboratory of Oncology, School of Life 5 cal Center, Cincinnati, Ohio. Department of Hematology, Sixth Hospital Science, Tokyo University of Pharmacy and Life Sciences, Tokyo, Japan; 6 Affi liated to Shanghai Jiaotong University, Shanghai, China. Key Labora- and current address for Y. Zhang: Henan University of Chinese Medicine, tory of Genomic and Precision Medicine, Collaborative Innovation Center Henan, China. of Genetics and Development, Beijing Institute of Genomics, Chinese Academy of Sciences, Beijing, China. 7 Division of Biomedical Informatics, Z. Xiao and G. Huang jointly supervised this work. Cincinnati Children’s Hospital Medical Center, Cincinnati, Ohio. 8 Division of Y. Hayashi, Y. Zhang, and A. Yokota contributed equally to this article. Immunobiology, Cincinnati Children’s Hospital Medical Center, Cincinnati, Corresponding Authors: Gang Huang, Cincinnati Children’s Hospital Medi- 9 Ohio. Laboratory of Oncology, School of Life Science, Tokyo University of cal Center, 3333 Burnet Avenue, Room S7.607, Cincinnati, OH 45229. 10 Pharmacy and Life Sciences, Tokyo, Japan. Department of Hematology and Phone: 513-636-3214; E-mail: [email protected] ; and Zhijian Xiao, Oncology, Chang Gung Memorial Hospital-Linkou and Chang Gung University [email protected] College of Medicine, Taoyuan, Taiwan. 11 James Graham Brown Cancer Center, University of Louisville Hospital, Louisville, Kentucky. 12 Division of Pul- doi: 10.1158/2159-8290.CD-17-1203 monary Biology, Cincinnati Children’s Hospital Medical Center, Cincinnati, © 2018 American Association for Cancer Research. 1438 | CANCER DISCOVERY NOVEMBER 2018 www.aacrjournals.org Downloaded from cancerdiscovery.aacrjournals.org on October 1, 2021. © 2018 American Association for Cancer Research. Published OnlineFirst August 23, 2018; DOI: 10.1158/2159-8290.CD-17-1203 Activation of HIF1A Signaling by Pseudohypoxia in MDS RESEARCH ARTICLE INTRODUCTION reveal fundamental insights into MDS pathogenesis and pre- sent novel opportunities for therapeutic intervention beyond Myelodysplastic syndromes (MDS) are a group of hetero- specific mutations for MDS. geneous clonal disorders that are characterized by ineffective Hypoxia-inducible factor-1α (HIF1A) is a critical transcrip- hematopoiesis and unilineage or multilineage dysplasia (1, 2). tion factor for the hypoxic response, angiogenesis, normal Because of its diversity and complexity, the pathogenesis of HSC regulation, and cancer development (8, 9). Importantly, MDS remains to be elucidated. Limited preclinical models HIF1A is also essential for the activation of innate and are available for dissecting the pathogenesis and testing new adaptive immunity (10). HIF1A is regulated by both oxygen- drugs, and each model has its limitations (3, 4). Stem-cell dependent and oxygen-independent mechanisms (11). HSCs transplantation is a curative strategy for MDS; however, few and progenitor cells (HSPC) isolated from patients with MDS patients are eligible for transplantation. Further elucida- display abnormal self-renewal and differentiation, and accu- tion of the pathogenesis of MDS and development of novel mulating clinical and research evidence suggests an impor- therapeutic strategies are needed. MDS are associated with tant role for systemic inflammation and immune activation mutations in chromatin-modifying enzymes, splicing fac- in MDS pathogenesis (12). Thus, we tested the impact of HIF1A tors, transcription factors, cohesin complex, and metabolic sig naling in MDS. enzymes that regulate hematopoietic stem cell (HSC) self- renewal, survival, and differentiation. Cooperating genetic lesions occur, involving signaling molecules that regulate RESULTS cell growth and proliferation (1, 2, 5). Although a number of heterogeneous genomic aberrations have been identified Activated HIF1A Pathway in a Broad in patients with MDS (6, 7), their key clinical phenotypes are Spectrum of Patients with MDS similar. Therefore, we hypothesized that driver mutations HIF1A is mainly regulated at translational and protein activate common underlying mechanisms involved in MDS levels. Thus, analyzing downstream HIF1A signature gene phenotypes. Identification of these key mediators would expression is a reliable approach to measure HIF1A activation. NOVEMBER 2018 CANCER DISCOVERY | 1439 Downloaded from cancerdiscovery.aacrjournals.org on October 1, 2021. © 2018 American Association for Cancer Research. Published OnlineFirst August 23, 2018; DOI: 10.1158/2159-8290.CD-17-1203 RESEARCH ARTICLE Hayashi et al. To determine whether patients with MDS have an activated achieved doxycycline-inducible expression of both a stable HIF1A gene signature, we analyzed a published cohort of and constitutively active human HIF1A triple-point-mutant CD34+ bone marrow (BM) cells isolated from healthy donors (TPM; ref. 16) and wild-type (WT) ARNT (also known as (n = 17) or from patients with MDS (n = 183; ref. 13). This HIF1B, a subunit for dimerization with HIF1A; tet-on-TPM/ MDS cohort contains patients with refractory anemia (RA; ARNT; B6J/129 × 1 SvJ; Fig. 2A). After doxycycline admin- n = 55), refractory anemia with ring sideroblasts (RARS; n = istration, we found increased HIF1A protein expression 48), or refractory anemia with excess blast type 1 (RAEB1; n = in the c-KIT+ BM cells from Vav1-Cre/TPM mice (Fig. 2B). 37) or type 2 (RAEB2; n = 43). HIF1A regulates many genes, The resulting HIF1A protein expression level was 1.5-fold which could be either HIF1A direct targets or indirect tar- higher than in MllPTD/WT cells (Fig. 2C). To identify gene- gets (such as those regulated by HIF1A-regulated miRNAs). expression changes, we performed RNA-sequencing (RNA- The number of HIF1A-regulated genes exceeds 1,000 and seq) analysis of Vav1-Cre/TPM and wild-type c-KIT+ BM continues to increase (11). Notably, there are unique sets of cells. Pathway enrichment analysis revealed that a number target genes activated by HIF1A signaling in individual cell of HIF1A-related gene sets were significantly upregulated types (different lineage, at different maturation stage; ref. in the c-KIT+ BM cells from Vav1-Cre/TPM mice
Load more

Recommended publications
  • RNA-Seq Alignment to Individualized Genomes Improves Transcript Abundance Estimates in Multiparent Populations
    MULTIPARENTAL POPULATIONS RNA-Seq Alignment to Individualized Genomes Improves Transcript Abundance Estimates in Multiparent Populations Steven C. Munger,* Narayanan Raghupathy,* Kwangbom Choi,* Allen K. Simons,* Daniel M. Gatti,* Douglas A. Hinerfeld,* Karen L. Svenson,* Mark P. Keller,† Alan D. Attie,† Matthew A. Hibbs,*,‡ Joel H. Graber,* Elissa J. Chesler,* and Gary A. Churchill*,1 *The Jackson Laboratory, Bar Harbor, Maine 04609, †University of Wisconsin, Madison, Wisconsin 53705, and ‡Trinity University, San Antonio, Texas 78212 ORCID ID: 0000-0002-8458-1871 (S.C.M.) ABSTRACT Massively parallel RNA sequencing (RNA-seq) has yielded a wealth of new insights into transcriptional regulation. A first step in the analysis of RNA-seq data is the alignment of short sequence reads to a common reference genome or transcriptome. Genetic variants that distinguish individual genomes from the reference sequence can cause reads to be misaligned, resulting in biased estimates of transcript abundance. Fine-tuning of read alignment algorithms does not correct this problem. We have developed Seqnature software to construct individualized diploid genomes and transcriptomes for multiparent populations and have implemented a complete analysis pipeline that incorporates other existing software tools. We demonstrate in simulated and real data sets that alignment to individualized transcriptomes increases read mapping accuracy, improves estimation of transcript abundance, and enables the direct estimation of allele-specific expression. Moreover, when applied to expression QTL mapping we find that our individualized alignment strategy corrects false-positive linkage signals and unmasks hidden associations. We recommend the use of individualized diploid genomes over reference sequence alignment for all applications of high-throughput sequencing technology in genetically diverse populations.
    [Show full text]
  • Integrating Single-Step GWAS and Bipartite Networks Reconstruction Provides Novel Insights Into Yearling Weight and Carcass Traits in Hanwoo Beef Cattle
    animals Article Integrating Single-Step GWAS and Bipartite Networks Reconstruction Provides Novel Insights into Yearling Weight and Carcass Traits in Hanwoo Beef Cattle Masoumeh Naserkheil 1 , Abolfazl Bahrami 1 , Deukhwan Lee 2,* and Hossein Mehrban 3 1 Department of Animal Science, University College of Agriculture and Natural Resources, University of Tehran, Karaj 77871-31587, Iran; [email protected] (M.N.); [email protected] (A.B.) 2 Department of Animal Life and Environment Sciences, Hankyong National University, Jungang-ro 327, Anseong-si, Gyeonggi-do 17579, Korea 3 Department of Animal Science, Shahrekord University, Shahrekord 88186-34141, Iran; [email protected] * Correspondence: [email protected]; Tel.: +82-31-670-5091 Received: 25 August 2020; Accepted: 6 October 2020; Published: 9 October 2020 Simple Summary: Hanwoo is an indigenous cattle breed in Korea and popular for meat production owing to its rapid growth and high-quality meat. Its yearling weight and carcass traits (backfat thickness, carcass weight, eye muscle area, and marbling score) are economically important for the selection of young and proven bulls. In recent decades, the advent of high throughput genotyping technologies has made it possible to perform genome-wide association studies (GWAS) for the detection of genomic regions associated with traits of economic interest in different species. In this study, we conducted a weighted single-step genome-wide association study which combines all genotypes, phenotypes and pedigree data in one step (ssGBLUP). It allows for the use of all SNPs simultaneously along with all phenotypes from genotyped and ungenotyped animals. Our results revealed 33 relevant genomic regions related to the traits of interest.
    [Show full text]
  • Atrazine and Cell Death Symbol Synonym(S)
    Supplementary Table S1: Atrazine and Cell Death Symbol Synonym(s) Entrez Gene Name Location Family AR AIS, Andr, androgen receptor androgen receptor Nucleus ligand- dependent nuclear receptor atrazine 1,3,5-triazine-2,4-diamine Other chemical toxicant beta-estradiol (8R,9S,13S,14S,17S)-13-methyl- Other chemical - 6,7,8,9,11,12,14,15,16,17- endogenous decahydrocyclopenta[a]phenanthrene- mammalian 3,17-diol CGB (includes beta HCG5, CGB3, CGB5, CGB7, chorionic gonadotropin, beta Extracellular other others) CGB8, chorionic gonadotropin polypeptide Space CLEC11A AW457320, C-type lectin domain C-type lectin domain family 11, Extracellular growth factor family 11, member A, STEM CELL member A Space GROWTH FACTOR CYP11A1 CHOLESTEROL SIDE-CHAIN cytochrome P450, family 11, Cytoplasm enzyme CLEAVAGE ENZYME subfamily A, polypeptide 1 CYP19A1 Ar, ArKO, ARO, ARO1, Aromatase cytochrome P450, family 19, Cytoplasm enzyme subfamily A, polypeptide 1 ESR1 AA420328, Alpha estrogen receptor,(α) estrogen receptor 1 Nucleus ligand- dependent nuclear receptor estrogen C18 steroids, oestrogen Other chemical drug estrogen receptor ER, ESR, ESR1/2, esr1/esr2 Nucleus group estrone (8R,9S,13S,14S)-3-hydroxy-13-methyl- Other chemical - 7,8,9,11,12,14,15,16-octahydro-6H- endogenous cyclopenta[a]phenanthren-17-one mammalian G6PD BOS 25472, G28A, G6PD1, G6PDX, glucose-6-phosphate Cytoplasm enzyme Glucose-6-P Dehydrogenase dehydrogenase GATA4 ASD2, GATA binding protein 4, GATA binding protein 4 Nucleus transcription TACHD, TOF, VSD1 regulator GHRHR growth hormone releasing
    [Show full text]
  • Análise Integrativa De Perfis Transcricionais De Pacientes Com
    UNIVERSIDADE DE SÃO PAULO FACULDADE DE MEDICINA DE RIBEIRÃO PRETO PROGRAMA DE PÓS-GRADUAÇÃO EM GENÉTICA ADRIANE FEIJÓ EVANGELISTA Análise integrativa de perfis transcricionais de pacientes com diabetes mellitus tipo 1, tipo 2 e gestacional, comparando-os com manifestações demográficas, clínicas, laboratoriais, fisiopatológicas e terapêuticas Ribeirão Preto – 2012 ADRIANE FEIJÓ EVANGELISTA Análise integrativa de perfis transcricionais de pacientes com diabetes mellitus tipo 1, tipo 2 e gestacional, comparando-os com manifestações demográficas, clínicas, laboratoriais, fisiopatológicas e terapêuticas Tese apresentada à Faculdade de Medicina de Ribeirão Preto da Universidade de São Paulo para obtenção do título de Doutor em Ciências. Área de Concentração: Genética Orientador: Prof. Dr. Eduardo Antonio Donadi Co-orientador: Prof. Dr. Geraldo A. S. Passos Ribeirão Preto – 2012 AUTORIZO A REPRODUÇÃO E DIVULGAÇÃO TOTAL OU PARCIAL DESTE TRABALHO, POR QUALQUER MEIO CONVENCIONAL OU ELETRÔNICO, PARA FINS DE ESTUDO E PESQUISA, DESDE QUE CITADA A FONTE. FICHA CATALOGRÁFICA Evangelista, Adriane Feijó Análise integrativa de perfis transcricionais de pacientes com diabetes mellitus tipo 1, tipo 2 e gestacional, comparando-os com manifestações demográficas, clínicas, laboratoriais, fisiopatológicas e terapêuticas. Ribeirão Preto, 2012 192p. Tese de Doutorado apresentada à Faculdade de Medicina de Ribeirão Preto da Universidade de São Paulo. Área de Concentração: Genética. Orientador: Donadi, Eduardo Antonio Co-orientador: Passos, Geraldo A. 1. Expressão gênica – microarrays 2. Análise bioinformática por module maps 3. Diabetes mellitus tipo 1 4. Diabetes mellitus tipo 2 5. Diabetes mellitus gestacional FOLHA DE APROVAÇÃO ADRIANE FEIJÓ EVANGELISTA Análise integrativa de perfis transcricionais de pacientes com diabetes mellitus tipo 1, tipo 2 e gestacional, comparando-os com manifestações demográficas, clínicas, laboratoriais, fisiopatológicas e terapêuticas.
    [Show full text]
  • 1St International Conference of Translational Medicine
    American Journal of Translational Medicine Vol 3 Issue 1, 2019 ISSN 2474-7378 (P) & 2474-7386 (O) A J CONFERENCE T M Proceedings of st 2 1 International Conference of Translational Medicine 0 1 You-Ping Deng1, JIanxin Gao2, Zhiqian Hu3, Zhong Li4, Guo-Tong Xu5, Gang-Ming Zou6 9 1University of Hawaii School of Medicine, Honolulu, USA 2Shanghai Jiao Tong University, Shanghai, China. 3Shanghai Changzheng Hospital, Shanghai, China 4Shanghai Cell Therapy Institute, Shanghai, China 5Tongji University, Shanghai, China 6American Journal of Translational Medicine. Honolulu, USA *Correspondence: G.M.Z. (email: [email protected]) Conference Chair: Gang-Ming Zou, MD, PhD Conference Co-Chair: Guo-Tong Xu, PhD Conference General Secretary: You-Ping Deng, PhD Programs: Program A Translational Oncology (Abstract A001-A019) Program leader: Zhi-qian Hu, MD Program B Stem cell and Regenerative medicine (Abstract B001-B012) Program leader Guo-Tong Xu, PhD Program C Medicine and Health (Abstract C001-C013) Program leader: Gang-Ming Zou, MD, PhD Scientific Advisors: Zhong-Chao Han (China). Zhi-Qian Hu (China), Victor Lobanenkov, PhD (USA), Organizing Committee: You-Ping Deng, PhD (USA), Cunyi Fan (China), Jian-Xin Gao, PhD (China), Zhi-Quan Hu, MD (China), Wen-Yang Hu, MD (USA), Zhong LI (China), Daniel Scherman, PhD, (France), Georges Uzan, PhD (France), Liaonan Zou, MD, PhD (China), Guo-Tong Xu (China), Gang-Ming Zou (USA), 1 Hawaii Gangze InC., Publisher, Honolulu, USA American Journal of Translational Medicine Vol 3 Issue 1, 2019 ISSN 2474-7378 (P) & 2474-7386 (O) Conference Committee: You-Ping Deng, PhD, Guo-Tong Xu, MD, Gang-Ming Zou, MD, PhD Finance Chair and Treasurer: You-Ping Deng PhD, Finance and Treasure Committee: You-Ping Deng PhD, Gang-Ming Zou, MD, PhD.
    [Show full text]
  • Behavioral and Brain Functions Biomed Central
    Behavioral and Brain Functions BioMed Central Research Open Access Selection for tameness modulates the expression of heme related genes in silver foxes Julia Lindberg1,3, Susanne Björnerfeldt1, Morten Bakken2, Carles Vilà1, Elena Jazin3 and Peter Saetre*3 Address: 1Department of Evolution, Genomics and Systematics, Uppsala University, Norbyvägen 18D, S-752 36 Uppsala, Sweden, 2Department of Animal and Aquacultural Sciences, Norwegian University of Life Science, P.O. Box 5003 N-1432 Aas, Norway and 3Department of Physiology and Developmental Biology, Uppsala University, Norbyvägen 18A, S-752 36 Uppsala, Sweden Email: Julia Lindberg - [email protected]; Susanne Björnerfeldt - [email protected]; Morten Bakken - [email protected]; Carles Vilà - [email protected]; Elena Jazin - [email protected]; Peter Saetre* - [email protected] * Corresponding author Published: 17 April 2007 Received: 24 January 2007 Accepted: 17 April 2007 Behavioral and Brain Functions 2007, 3:18 doi:10.1186/1744-9081-3-18 This article is available from: http://www.behavioralandbrainfunctions.com/content/3/1/18 © 2007 Lindberg et al; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Abstract Background: The genetic and molecular mechanisms of tameness are largely unknown. A line of silver foxes (Vulpes vulpes) selected for non-aggressive behavior has been used in Russia since the 1960's to study the effect of domestication. We have previously compared descendants of these selected (S) animals with a group of non-selected (NS) silver foxes kept under identical conditions, and showed that changes in the brain transcriptome between the two groups are small.
    [Show full text]
  • Progression of Pathology in PINK1-Deficient Mouse Brain From
    Torres-Odio et al. Journal of Neuroinflammation (2017) 14:154 DOI 10.1186/s12974-017-0928-0 RESEARCH Open Access Progression of pathology in PINK1-deficient mouse brain from splicing via ubiquitination, ER stress, and mitophagy changes to neuroinflammation Sylvia Torres-Odio1†, Jana Key1†, Hans-Hermann Hoepken1, Júlia Canet-Pons1, Lucie Valek2, Bastian Roller3, Michael Walter4, Blas Morales-Gordo5, David Meierhofer6, Patrick N. Harter3, Michel Mittelbronn3,7,8,9,10, Irmgard Tegeder2, Suzana Gispert1 and Georg Auburger1* Abstract Background: PINK1 deficiency causes the autosomal recessive PARK6 variant of Parkinson’s disease. PINK1 activates ubiquitin by phosphorylation and cooperates with the downstream ubiquitin ligase PARKIN, to exert quality control and control autophagic degradation of mitochondria and of misfolded proteins in all cell types. Methods: Global transcriptome profiling of mouse brain and neuron cultures were assessed in protein-protein interaction diagrams and by pathway enrichment algorithms. Validation by quantitative reverse transcriptase polymerase chain reaction and immunoblots was performed, including human neuroblastoma cells and patient primary skin fibroblasts. Results: In a first approach, we documented Pink1-deleted mice across the lifespan regarding brain mRNAs. The expression changes were always subtle, consistently affecting “intracellular membrane-bounded organelles”.Significant anomalies involved about 250 factors at age 6 weeks, 1300 at 6 months, and more than 3500 at age 18 months in the cerebellar tissue, including Srsf10, Ube3a, Mapk8, Creb3,andNfkbia. Initially, mildly significant pathway enrichment for the spliceosome was apparent. Later, highly significant networks of ubiquitin-mediated proteolysis and endoplasmic reticulum protein processing occurred. Finally, an enrichment of neuroinflammation factors appeared, together with profiles of bacterial invasion and MAPK signaling changes—while mitophagy had minor significance.
    [Show full text]
  • Genome-Wide Insights on Gastrointestinal Nematode
    www.nature.com/scientificreports OPEN Genome‑wide insights on gastrointestinal nematode resistance in autochthonous Tunisian sheep A. M. Ahbara1,2, M. Rouatbi3,4, M. Gharbi3,4, M. Rekik1, A. Haile1, B. Rischkowsky1 & J. M. Mwacharo1,5* Gastrointestinal nematode (GIN) infections have negative impacts on animal health, welfare and production. Information from molecular studies can highlight the underlying genetic mechanisms that enhance host resistance to GIN. However, such information often lacks for traditionally managed indigenous livestock. Here, we analysed 600 K single nucleotide polymorphism genotypes of GIN infected and non‑infected traditionally managed autochthonous Tunisian sheep grazing communal natural pastures. Population structure analysis did not fnd genetic diferentiation that is consistent with infection status. However, by contrasting the infected versus non‑infected cohorts using ROH, LR‑GWAS, FST and XP‑EHH, we identifed 35 candidate regions that overlapped between at least two methods. Nineteen regions harboured QTLs for parasite resistance, immune capacity and disease susceptibility and, ten regions harboured QTLs for production (growth) and meat and carcass (fatness and anatomy) traits. The analysis also revealed candidate regions spanning genes enhancing innate immune defence (SLC22A4, SLC22A5, IL‑4, IL‑13), intestinal wound healing/repair (IL‑4, VIL1, CXCR1, CXCR2) and GIN expulsion (IL‑4, IL‑13). Our results suggest that traditionally managed indigenous sheep have evolved multiple strategies that evoke and enhance GIN resistance and developmental stability. They confrm the importance of obtaining information from indigenous sheep to investigate genomic regions of functional signifcance in understanding the architecture of GIN resistance. Small ruminants (sheep and goats) make immense socio-economic and cultural contributions across the globe.
    [Show full text]
  • Increased Expression of Heme-Binding Protein 1 Early In
    RESEARCH ARTICLE Increased expression of heme-binding protein 1 early in Alzheimer’s disease is linked to neurotoxicity Oleksandr Yagensky1*, Mahdokht Kohansal-Nodehi2†, Saravanan Gunaseelan3†, Tamara Rabe4, Saima Zafar5,6, Inga Zerr6, Wolfgang Ha¨ rtig7, Henning Urlaub8,9, John JE Chua1,3,10,11,12* 1Research Group Protein Trafficking in Synaptic Development and Function, Max Planck Institute for Biophysical Chemistry, Go¨ ttingen, Germany; 2Department of Neurobiology, Max Planck Institute for Biophysical Chemistry, Go¨ ttingen, Germany; 3Interactomics and Intracellular Trafficking Laboratory, Department of Physiology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore; 4Department of Genes and Behavior, Max Planck Institute for Biophysical Chemistry, Go¨ ttingen, Germany; 5Biomedical Engineering and Sciences Department, School of Mechanical and Manufacturing Engineering (SMME), National University of Sciences and Technology (NUST), Islamabad, Pakistan; 6Clinical Dementia Center, Department of Neurology, German Center for Neurodegenerative Diseases, University Medical Center Go¨ ttingen, Go¨ ttingen, Germany; 7Paul Flechsig Institute for Brain Research, University of Leipzig, Leipzig, Germany; 8Research Group Bioanalytical Mass Spectrometry, Max Planck Institute for Biophysical Chemistry, Go¨ ttingen, Germany; 9Bioanalytics Group, Institute for Clinical Chemistry, University Medical Center Go¨ ttingen, Go¨ ttingen, Germany; 10LSI Neurobiology Programme, National University of Singapore, Singapore,
    [Show full text]
  • About the Contributors
    403 About the Contributors Jinglong Wu was born in Jiutai, China, on August 8, 1958. He received a BS from Jilin Vocational Teachers College, China, and MS from Kyoto University, Japan, both in electrical engineering, in 1984 and 1991, respectively. He received his PhD in electric engineering from Kyoto University, Japan, in 1994. He was an assistant professor at Ritsumeikan University, Japan, from 1994 to 1997, a lecturer in the Department of Mechanical Engineering, Faculty of Engineering, Yamaguchi University, from 1997 to 1999. From 1999, he was an associate professor, and from 2002, he was a full professor in the Depart- ment of Intelligent Mechanical Systems, Faculty of Engineering, Kagawa University, Japan. Since 2008, he has been Professor and Laboratory Head, Biomedical Engineering Laboratory, Graduate School of Natural Science and Technology, Okayama University, Japan. His current research interests are bio- medical engineering, cognitive neuroscience, ergonomics and human science. Dr. Wu received the Best Paper Award of the IEEE Joint International Conference on Neural Network in 1993 and the SICE Best Paper Award in 2000. In 2003, he received the Gennai Grand Prize, Ozaki Foundation, Japan. * * * Koji Abe is 53 years old and is currently Professor and Chairman of Neurology at Okayama University Medical School in Japan. He graduated from Tohoku University School of Medicine (M.D.) in Sendai (Japan) and then received a PhD from Tohoku University. Professor Koji Abe has published more than 400 papers on clinical neurology, translational stroke research, and the discovery of many genes involved in neurological diseases (e.g., Alzheimer’s, amyotrophic lateral sclerosis, and Parkinson’s diseases), all of which are deeply related to dementia.
    [Show full text]
  • Robles JTO Supplemental Digital Content 1
    Supplementary Materials An Integrated Prognostic Classifier for Stage I Lung Adenocarcinoma based on mRNA, microRNA and DNA Methylation Biomarkers Ana I. Robles1, Eri Arai2, Ewy A. Mathé1, Hirokazu Okayama1, Aaron Schetter1, Derek Brown1, David Petersen3, Elise D. Bowman1, Rintaro Noro1, Judith A. Welsh1, Daniel C. Edelman3, Holly S. Stevenson3, Yonghong Wang3, Naoto Tsuchiya4, Takashi Kohno4, Vidar Skaug5, Steen Mollerup5, Aage Haugen5, Paul S. Meltzer3, Jun Yokota6, Yae Kanai2 and Curtis C. Harris1 Affiliations: 1Laboratory of Human Carcinogenesis, NCI-CCR, National Institutes of Health, Bethesda, MD 20892, USA. 2Division of Molecular Pathology, National Cancer Center Research Institute, Tokyo 104-0045, Japan. 3Genetics Branch, NCI-CCR, National Institutes of Health, Bethesda, MD 20892, USA. 4Division of Genome Biology, National Cancer Center Research Institute, Tokyo 104-0045, Japan. 5Department of Chemical and Biological Working Environment, National Institute of Occupational Health, NO-0033 Oslo, Norway. 6Genomics and Epigenomics of Cancer Prediction Program, Institute of Predictive and Personalized Medicine of Cancer (IMPPC), 08916 Badalona (Barcelona), Spain. List of Supplementary Materials Supplementary Materials and Methods Fig. S1. Hierarchical clustering of based on CpG sites differentially-methylated in Stage I ADC compared to non-tumor adjacent tissues. Fig. S2. Confirmatory pyrosequencing analysis of DNA methylation at the HOXA9 locus in Stage I ADC from a subset of the NCI microarray cohort. 1 Fig. S3. Methylation Beta-values for HOXA9 probe cg26521404 in Stage I ADC samples from Japan. Fig. S4. Kaplan-Meier analysis of HOXA9 promoter methylation in a published cohort of Stage I lung ADC (J Clin Oncol 2013;31(32):4140-7). Fig. S5. Kaplan-Meier analysis of a combined prognostic biomarker in Stage I lung ADC.
    [Show full text]
  • Cell-Type–Specific Eqtl of Primary Melanocytes Facilitates Identification of Melanoma Susceptibility Genes
    Downloaded from genome.cshlp.org on September 26, 2021 - Published by Cold Spring Harbor Laboratory Press Research Cell-type–specific eQTL of primary melanocytes facilitates identification of melanoma susceptibility genes Tongwu Zhang,1,7 Jiyeon Choi,1,7 Michael A. Kovacs,1 Jianxin Shi,2 Mai Xu,1 NISC Comparative Sequencing Program,9 Melanoma Meta-Analysis Consortium,10 Alisa M. Goldstein,3 Adam J. Trower,4 D. Timothy Bishop,4 Mark M. Iles,4 David L. Duffy,5 Stuart MacGregor,5 Laufey T. Amundadottir,1 Matthew H. Law,5 Stacie K. Loftus,6 William J. Pavan,6,8 and Kevin M. Brown1,8 1Laboratory of Translational Genomics, Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892, USA; 2Biostatistics Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892, USA; 3Clinical Genetics Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892, USA; 4Section of Epidemiology and Biostatistics, Leeds Institute of Cancer and Pathology, University of Leeds, Leeds, LS9 7TF, United Kingdom; 5Statistical Genetics, QIMR Berghofer Medical Research Institute, Brisbane, Queensland, 4006, Australia; 6Genetic Disease Research Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland 20892, USA Most expression quantitative trait locus (eQTL) studies to date have been performed in heterogeneous tissues as opposed to specific cell types. To better understand the cell-type–specific regulatory landscape of human melanocytes, which give rise to melanoma but account for <5% of typical human skin biopsies, we performed an eQTL analysis in primary melanocyte cul- tures from 106 newborn males.
    [Show full text]