16P11.2 Transcription Factor MAZ Is a Dosage-Sensitive Regulator Of
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Single Nucleotide Polymorphisms in DKK3 Gene Are Associated with Prostate Cancer Risk and Progression ______
ORIGINAL ARTICLE Vol. 41 (5): 869-897, September - October, 2015 doi: 10.1590/S1677-5538.IBJU.2014.0041 Single nucleotide polymorphisms in DKK3 gene are associated with prostate cancer risk and progression _______________________________________________ Min Su Kim 1, Ha Na Lee 2, Hae Jong Kim 3,4, Soon Chul Myung 5 1Department of Urology, Seoul Medical Center, Seoul, Korea; 2Department of Urology, Seoul Seonam Hospital, EwhaWomans University, Seoul, Korea; 3Research Institue for Biomedical and Pharmaceutical Sciences, Chung-Ang University, Seoul, Korea; 4Advanced Urogenital Diseas Research Center, Chung-Ang University, College of Medicine, Seoul, Korea; 5Department of Urology, Chung-Ang University, College of Medicine, Seoul, Korea ABSTRACT ARTICLE INFO ______________________________________________________________ ______________________ We had investigated whether sequence variants within DKK3 gene are associated with Key words: the development of prostate cancer in a Korean study cohort. We evaluated the asso- Biological Markers; Genetic ciation between 53 single nucleotide polymorphisms (SNPs) in the DKK3 gene and Variation; Prostatic Neoplasms; prostate cancer risk as well as clinical characteristics (PSA, clinical stage, pathological Polymorphism, Single Nucleotide stage and Gleason score) in Korean men (272 prostate cancer subjects and 173 benign prostate hyperplasia subjects) using unconditional logistic regression analysis. Of the Int Braz J Urol. 2015; 41: 869-97 53 SNPs and 25 common haplotypes, 5 SNPs and 4 haplotypes were -
Short Bowel Syndrome Results in Increased Gene Expression
Schall et al. BMC Genomics (2017) 18:23 DOI 10.1186/s12864-016-3433-4 RESEARCH ARTICLE Open Access Short bowel syndrome results in increased gene expression associated with proliferation, inflammation, bile acid synthesis and immune system activation: RNA sequencing a zebrafish SBS model Kathy A. Schall1, Matthew E. Thornton2, Mubina Isani1, Kathleen A. Holoyda1, Xiaogang Hou1, Ching-Ling Lien3, Brendan H. Grubbs2 and Tracy C. Grikscheit1,4* Abstract Background: Much of the morbidity associated with short bowel syndrome (SBS) is attributed to effects of decreased enteral nutrition and administration of total parenteral nutrition (TPN). We hypothesized that acute SBS alone has significant effects on gene expression beyond epithelial proliferation, and tested this in a zebrafish SBS model. Methods: In a model of SBS in zebrafish (laparotomy, proximal stoma, distal ligation, n = 29) or sham (laparotomy alone, n = 28) surgery, RNA-Seq was performed after 2 weeks. The proximal intestine was harvested and RNA isolated. The three samples from each group with the highest amount of RNA were spiked with external RNA controls consortium (ERCC) controls, sequenced and aligned to reference genome with gene ontology (GO) enrichment analysis performed. Gene expression of ctnnb1, ccnb1, ccnd1, cyp7a1a, dkk3, ifng1-2, igf2a, il1b, lef1, nos2b, saa1, stat3, tnfa and wnt5a were confirmed to be elevated in SBS by RT-qPCR. Results: RNA-seq analysis identified 1346 significantly upregulated genes and 678 significantly downregulated genes in SBS zebrafish intestine compared to sham with Ingenuity analysis. The upregulated genes were involved in cell proliferation, acute phase response signaling, innate and adaptive immunity, bile acid regulation, production of nitric oxide and reactive oxygen species, cellular barrier and coagulation. -
Distant Bystander Effect of REIC/DKK3 Gene Therapy Through Immune System Stimulation in Thoracic Malignancies
ANTICANCER RESEARCH 37 : 301-308 (2017) doi:10.21873/anticanres.11321 Distant Bystander Effect of REIC/DKK3 Gene Therapy Through Immune System Stimulation in Thoracic Malignancies KEN SUZAWA 1* , KAZUHIKO SHIEN 1,2* , HUANG PENG 3, MASAKIYO SAKAGUCHI 4, MASAMI WATANABE 5,6,7 , SHINSUKE HASHIDA 1,2 , YUHO MAKI 1, HIROMASA YAMAMOTO 1, SHUTA TOMIDA 8, JUNICHI SOH 1, HIROAKI ASANO 1, KAZUNORI TSUKUDA 1, YASUTOMO NASU 5,6,7 , HIROMI KUMON 3,5,7 , SHINICHIRO MIYOSHI 1 and SHINICHI TOYOOKA 1,2 Departments of 1Thoracic Surgery, 2Clinical Genomic Medicine and 4Cell Biology, 5Urology, 3Collaborative Research Center for Okayama Medical Innovation Center, and 8Biobank, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan; 6Center for Innovative Clinical Medicine, Okayama University Hospital, Okayama, Japan; 7Innovation Center Okayama for Nanobio-Targeted Therapy, Okayama University, Okayama, Japan Abstract. Background: Reduced expression in immortalized Both advanced-stage non-small cell lung cancer (NSCLC) cell (REIC)/Dickkoph-3 (DKK3) is a tumor-suppressor gene, and malignant mesothelioma (MM) are aggressive tumors and and its overexpression by adenovirus vector (Ad-REIC) present a dismal prognosis. Despite advances in treatment exhibits a remarkable therapeutic effect on various human regimens for both diseases, such as surgical resection, cancer types through a mechanism triggered by endoplasmic chemotherapy, molecular-targeted therapy and radiotherapy, reticulum stress. Materials and Methods: We examined the treatment outcome is still unsatisfactory. Gene therapy for direct anti-tumor effect of Ad-REIC gene therapy on lung thoracic malignancies represents a novel therapeutic approach cancer and malignant mesothelioma cell lines in vitro, and and has been evaluated in a number of clinical trials over the the distant bystander effect using immunocompetent mouse last two decades (1). -
Autism Multiplex Family with 16P11.2P12.2 Microduplication Syndrome in Monozygotic Twins and Distal 16P11.2 Deletion in Their Brother
European Journal of Human Genetics (2012) 20, 540–546 & 2012 Macmillan Publishers Limited All rights reserved 1018-4813/12 www.nature.com/ejhg ARTICLE Autism multiplex family with 16p11.2p12.2 microduplication syndrome in monozygotic twins and distal 16p11.2 deletion in their brother Anne-Claude Tabet1,2,3,4, Marion Pilorge2,3,4, Richard Delorme5,6,Fre´de´rique Amsellem5,6, Jean-Marc Pinard7, Marion Leboyer6,8,9, Alain Verloes10, Brigitte Benzacken1,11,12 and Catalina Betancur*,2,3,4 The pericentromeric region of chromosome 16p is rich in segmental duplications that predispose to rearrangements through non-allelic homologous recombination. Several recurrent copy number variations have been described recently in chromosome 16p. 16p11.2 rearrangements (29.5–30.1 Mb) are associated with autism, intellectual disability (ID) and other neurodevelopmental disorders. Another recognizable but less common microdeletion syndrome in 16p11.2p12.2 (21.4 to 28.5–30.1 Mb) has been described in six individuals with ID, whereas apparently reciprocal duplications, studied by standard cytogenetic and fluorescence in situ hybridization techniques, have been reported in three patients with autism spectrum disorders. Here, we report a multiplex family with three boys affected with autism, including two monozygotic twins carrying a de novo 16p11.2p12.2 duplication of 8.95 Mb (21.28–30.23 Mb) characterized by single-nucleotide polymorphism array, encompassing both the 16p11.2 and 16p11.2p12.2 regions. The twins exhibited autism, severe ID, and dysmorphic features, including a triangular face, deep-set eyes, large and prominent nasal bridge, and tall, slender build. The eldest brother presented with autism, mild ID, early-onset obesity and normal craniofacial features, and carried a smaller, overlapping 16p11.2 microdeletion of 847 kb (28.40–29.25 Mb), inherited from his apparently healthy father. -
Leveraging Mouse Chromatin Data for Heritability Enrichment Informs Common Disease Architecture and Reveals Cortical Layer Contributions to Schizophrenia
Downloaded from genome.cshlp.org on October 5, 2021 - Published by Cold Spring Harbor Laboratory Press Research Leveraging mouse chromatin data for heritability enrichment informs common disease architecture and reveals cortical layer contributions to schizophrenia Paul W. Hook1 and Andrew S. McCallion1,2,3 1McKusick-Nathans Department of Genetic Medicine, 2Department of Comparative and Molecular Pathobiology, 3Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA Genome-wide association studies have implicated thousands of noncoding variants across common human phenotypes. However, they cannot directly inform the cellular context in which disease-associated variants act. Here, we use open chro- matin profiles from discrete mouse cell populations to address this challenge. We applied stratified linkage disequilibrium score regression and evaluated heritability enrichment in 64 genome-wide association studies, emphasizing schizophrenia. We provide evidence that mouse-derived human open chromatin profiles can serve as powerful proxies for difficult to ob- tain human cell populations, facilitating the illumination of common disease heritability enrichment across an array of hu- man phenotypes. We demonstrate that signatures from discrete subpopulations of cortical excitatory and inhibitory neurons are significantly enriched for schizophrenia heritability with maximal enrichment in cortical layer V excitatory neu- rons. We also show that differences between schizophrenia and bipolar disorder are concentrated in excitatory neurons in cortical layers II-III, IV, and V, as well as the dentate gyrus. Finally, we leverage these data to fine-map variants in 177 schiz- ophrenia loci nominating variants in 104/177. We integrate these data with transcription factor binding site, chromatin in- teraction, and validated enhancer data, placing variants in the cellular context where they may modulate risk. -
In Human Metabolism
Supporting Information (SI Appendix) Framework and resource for more than 11,000 gene-transcript- protein-reaction associations (GeTPRA) in human metabolism SI Appendix Materials and Methods Standardization of Metabolite IDs with MNXM IDs Defined in the MNXref Namespace. Information on metabolic contents of the Recon 2Q was standardized using MNXM IDs defined in the MNXref namespace available at MetaNetX (1-3). This standardization was to facilitate the model refinement process described below. Each metabolite ID in the Recon 2Q was converted to MNXM ID accordingly. For metabolite IDs that were not converted to MNXM IDs, they were manually converted to MNXM IDs by comparing their compound structures and synonyms. In the final resulting SBML files, 97 metabolites were assigned with arbitrary IDs (i.e., “MNXMK_” followed by four digits) because they were not covered by the MNXref namespace (i.e., metabolite IDs not converted to MNXM IDs). Refinement or Removal of Biochemically Inconsistent Reactions. Recon 2 was built upon metabolic genes and reactions collected from EHMN (4, 5), the first genome-scale human liver metabolic model HepatoNet1 (6), an acylcarnitine and fatty-acid oxidation model Ac-FAO (7), and a small intestinal enterocyte model hs_eIEC611 (8). Flux variability analysis (9) of the Recon 2Q identified blocked reactions coming from these four sources of metabolic reaction data. The EHMN caused the greatest number of blocked reactions in the Recon 2Q (1,070 reactions corresponding to 69.3% of all the identified blocked reactions). To refine the EHMN reactions, following reactions were initially disregarded: 1) reactions having metabolite IDs not convertible to MNXM IDs; and 2) reactions without genes. -
Identification of Genetic Variants in CFAP221 As a Cause of Primary Ciliary Dyskinesia
HHS Public Access Author manuscript Author ManuscriptAuthor Manuscript Author J Hum Genet Manuscript Author . Author manuscript; Manuscript Author available in PMC 2020 April 21. Published in final edited form as: J Hum Genet. 2020 January ; 65(2): 175–180. doi:10.1038/s10038-019-0686-1. Identification of Genetic Variants in CFAP221 as a Cause of Primary Ciliary Dyskinesia Ximena M. Bustamante-Marin1,#, Adam Shapiro2,#, Patrick R. Sears1, Wu-Lin Charng3, Donald F. Conrad3,4, Margaret W. Leigh5, Michael R. Knowles1, Lawrence E. Ostrowski1,*, Maimoona A. Zariwala6,* 1Department of Medicine, Marsico Lung Institute, University of North Carolina, Chapel Hill, North Carolina., NC 27599, USA. 2Department of Pediatrics, Division of Pediatric Respiratory Medicine, McGill University Health Centre Research Institute, Montreal, Quebec. 3Department of Genetics and Psychiatry, Washington University School of Medicine, St. Louis, MO 63110, USA 4Division of Genetics, Oregon National Primate Research Center, Beaverton, OR, 97006, USA 5Department of Pediatrics, Marsico Lung Institute, University of North Carolina, Chapel Hill, North Carolina, 27599. 6Department of Pathology and Laboratory Medicine, Marsico Lung Institute University of North Carolina, Chapel Hill, NC 27599, USA. Abstract Users may view, print, copy, and download text and data-mine the content in such documents, for the purposes of academic research, subject always to the full Conditions of use:http://www.nature.com/authors/editorial_policies/license.html#terms * Corresponding Author: Lawrence E. Ostrowski, 104 Manning Dr Room 6021, [email protected], Phone: 919-8437177, Maimoona A. Zariwala, 7219 A Marsico Hall, [email protected], Phone: 919-966-7050, Fax: 919-966-5178. #Ximena M. Bustamante-Marin and Adam Shapiro are co-first authors. -
A KMT2A-AFF1 Gene Regulatory Network Highlights the Role of Core Transcription Factors and Reveals the Regulatory Logic of Key Downstream Target Genes
Downloaded from genome.cshlp.org on October 7, 2021 - Published by Cold Spring Harbor Laboratory Press Research A KMT2A-AFF1 gene regulatory network highlights the role of core transcription factors and reveals the regulatory logic of key downstream target genes Joe R. Harman,1,7 Ross Thorne,1,7 Max Jamilly,2 Marta Tapia,1,8 Nicholas T. Crump,1 Siobhan Rice,1,3 Ryan Beveridge,1,4 Edward Morrissey,5 Marella F.T.R. de Bruijn,1 Irene Roberts,3,6 Anindita Roy,3,6 Tudor A. Fulga,2,9 and Thomas A. Milne1,6 1MRC Molecular Haematology Unit, MRC Weatherall Institute of Molecular Medicine, Radcliffe Department of Medicine, University of Oxford, Oxford, OX3 9DS, United Kingdom; 2MRC Weatherall Institute of Molecular Medicine, Radcliffe Department of Medicine, University of Oxford, Oxford, OX3 9DS, United Kingdom; 3MRC Molecular Haematology Unit, MRC Weatherall Institute of Molecular Medicine, Department of Paediatrics, University of Oxford, Oxford, OX3 9DS, United Kingdom; 4Virus Screening Facility, MRC Weatherall Institute of Molecular Medicine, John Radcliffe Hospital, University of Oxford, Oxford, OX3 9DS, United Kingdom; 5Center for Computational Biology, Weatherall Institute of Molecular Medicine, University of Oxford, John Radcliffe Hospital, Oxford OX3 9DS, United Kingdom; 6NIHR Oxford Biomedical Research Centre Haematology Theme, University of Oxford, Oxford, OX3 9DS, United Kingdom Regulatory interactions mediated by transcription factors (TFs) make up complex networks that control cellular behavior. Fully understanding these gene regulatory networks (GRNs) offers greater insight into the consequences of disease-causing perturbations than can be achieved by studying single TF binding events in isolation. Chromosomal translocations of the lysine methyltransferase 2A (KMT2A) gene produce KMT2A fusion proteins such as KMT2A-AFF1 (previously MLL-AF4), caus- ing poor prognosis acute lymphoblastic leukemias (ALLs) that sometimes relapse as acute myeloid leukemias (AMLs). -
A Rare Duplication on Chromosome 16P11.2 Is Identified in Patients with Psychosis in Alzheimer’S Disease
A Rare Duplication on Chromosome 16p11.2 Is Identified in Patients with Psychosis in Alzheimer’s Disease Xiaojing Zheng1,7*, F. Yesim Demirci2, M. Michael Barmada2, Gale A. Richardson3,6, Oscar L. Lopez4,5, Robert A. Sweet3,4,5, M. Ilyas Kamboh2,3,5, Eleanor Feingold1,2 1 Department of Biostatistics, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, Pennsylvania, United States of America, 2 Department of Human Genetics, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, Pennsylvania, United States of America, 3 Department of Psychiatry, School of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania, United States of America, 4 Department of Neurology, School of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania, United States of America, 5 VISN 4 Mental Illness Research, Education and Clinical Center, VA Pittsburgh Healthcare System, Pittsburgh, Pennsylvania, United States of America, 6 Department of Epidemiology, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, Pennsylvania, United States of America, 7 Department of Pediatrics, School of Medicine, University of North Carolina, Chapel Hill, North Carolina, United States of America Abstract Epidemiological and genetic studies suggest that schizophrenia and autism may share genetic links. Besides common single nucleotide polymorphisms, recent data suggest that some rare copy number variants (CNVs) are risk factors for both disorders. Because we have previously found that schizophrenia and psychosis in Alzheimer’s disease (AD+P) share some genetic risk, we investigated whether CNVs reported in schizophrenia and autism are also linked to AD+P. We searched for CNVs associated with AD+P in 7 recurrent CNV regions that have been previously identified across autism and schizophrenia, using the Illumina HumanOmni1-Quad BeadChip. -
Transcriptomic and Epigenomic Characterization of the Developing Bat Wing
ARTICLES OPEN Transcriptomic and epigenomic characterization of the developing bat wing Walter L Eckalbar1,2,9, Stephen A Schlebusch3,9, Mandy K Mason3, Zoe Gill3, Ash V Parker3, Betty M Booker1,2, Sierra Nishizaki1,2, Christiane Muswamba-Nday3, Elizabeth Terhune4,5, Kimberly A Nevonen4, Nadja Makki1,2, Tara Friedrich2,6, Julia E VanderMeer1,2, Katherine S Pollard2,6,7, Lucia Carbone4,8, Jeff D Wall2,7, Nicola Illing3 & Nadav Ahituv1,2 Bats are the only mammals capable of powered flight, but little is known about the genetic determinants that shape their wings. Here we generated a genome for Miniopterus natalensis and performed RNA-seq and ChIP-seq (H3K27ac and H3K27me3) analyses on its developing forelimb and hindlimb autopods at sequential embryonic stages to decipher the molecular events that underlie bat wing development. Over 7,000 genes and several long noncoding RNAs, including Tbx5-as1 and Hottip, were differentially expressed between forelimb and hindlimb, and across different stages. ChIP-seq analysis identified thousands of regions that are differentially modified in forelimb and hindlimb. Comparative genomics found 2,796 bat-accelerated regions within H3K27ac peaks, several of which cluster near limb-associated genes. Pathway analyses highlighted multiple ribosomal proteins and known limb patterning signaling pathways as differentially regulated and implicated increased forelimb mesenchymal condensation in differential growth. In combination, our work outlines multiple genetic components that likely contribute to bat wing formation, providing insights into this morphological innovation. The order Chiroptera, commonly known as bats, is the only group of To characterize the genetic differences that underlie divergence in mammals to have evolved the capability of flight. -
Transcriptome Profiling and Differential Gene Expression In
G C A T T A C G G C A T genes Article Transcriptome Profiling and Differential Gene Expression in Canine Microdissected Anagen and Telogen Hair Follicles and Interfollicular Epidermis Dominique J. Wiener 1,* ,Kátia R. Groch 1 , Magdalena A.T. Brunner 2,3, Tosso Leeb 2,3 , Vidhya Jagannathan 2 and Monika M. Welle 3,4 1 Department of Veterinary Pathobiology, College of Veterinary Medicine & Biomedical Science, Texas A&M University, College Station, TX 77843, USA; [email protected] 2 Institute of Genetics, Vetsuisse Faculty, University of Bern, 3012 Bern, Switzerland; [email protected] (M.A.T.B.); [email protected] (T.L.); [email protected] (V.J.) 3 Dermfocus, Vetsuisse Faculty, University Hospital of Bern, 3010 Bern, Switzerland; [email protected] 4 Institute of Animal Pathology, Vetsuisse Faculty, University of Bern, 3012 Bern, Switzerland * Correspondence: [email protected]; Tel.: +1-979-862-1568 Received: 30 June 2020; Accepted: 3 August 2020; Published: 4 August 2020 Abstract: The transcriptome profile and differential gene expression in telogen and late anagen microdissected hair follicles and the interfollicular epidermis of healthy dogs was investigated by using RNAseq. The genes with the highest expression levels in each group were identified and genes known from studies in other species to be associated with structure and function of hair follicles and epidermis were evaluated. Transcriptome profiling revealed that late anagen follicles expressed mainly keratins and telogen follicles expressed GSN and KRT15. The interfollicular epidermis expressed predominately genes encoding for proteins associated with differentiation. All sample groups express genes encoding for proteins involved in cellular growth and signal transduction. -
Dickkopf-3 Links HSF1 and YAP/TAZ Signalling to Control Aggressive Behaviours in Cancer-Associated fibroblasts
ARTICLE https://doi.org/10.1038/s41467-018-07987-0 OPEN Dickkopf-3 links HSF1 and YAP/TAZ signalling to control aggressive behaviours in cancer-associated fibroblasts Nicola Ferrari 1,8, Romana Ranftl1, Ievgeniia Chicherova1, Neil D. Slaven2, Emad Moeendarbary3,4, Aaron J. Farrugia1, Maxine Lam1, Maria Semiannikova1, Marie C. W. Westergaard5, Julia Tchou6, Luca Magnani 2 & Fernando Calvo1,7 1234567890():,; Aggressive behaviours of solid tumours are highly influenced by the tumour microenviron- ment. Multiple signalling pathways can affect the normal function of stromal fibroblasts in tumours, but how these events are coordinated to generate tumour-promoting cancer- associated fibroblasts (CAFs) is not well understood. Here we show that stromal expression of Dickkopf-3 (DKK3) is associated with aggressive breast, colorectal and ovarian cancers. We demonstrate that DKK3 is a HSF1 effector that modulates the pro-tumorigenic behaviour of CAFs in vitro and in vivo. DKK3 orchestrates a concomitant activation of β-catenin and YAP/TAZ. Whereas β-catenin is dispensable for CAF-mediated ECM remodelling, cancer cell growth and invasion, DKK3-driven YAP/TAZ activation is required to induce tumour- promoting phenotypes. Mechanistically, DKK3 in CAFs acts via canonical Wnt signalling by interfering with the negative regulator Kremen and increasing cell-surface levels of LRP6. This work reveals an unpredicted link between HSF1, Wnt signalling and YAP/TAZ relevant for the generation of tumour-promoting CAFs. 1 Tumour Microenvironment Team, Division of Cancer Biology, The Institute of Cancer Research, London SW3 6JB, UK. 2 Department of Surgery and Cancer, Imperial College London, London W12 0NN, UK. 3 Department of Mechanical Engineering, University College London, London WC1E 7JE, UK.