METTL16, Methyltransferase-Like Protein 16: Current Insights Into Structure and Function
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Amplification of 8Q21 in Breast Cancer Is Independent of MYC and Associated with Poor Patient Outcome
Modern Pathology (2010) 23, 603–610 & 2010 USCAP, Inc. All rights reserved 0893-3952/10 $32.00 603 Amplification of 8q21 in breast cancer is independent of MYC and associated with poor patient outcome Matthias Choschzick1, Paula Lassen1, Annette Lebeau1, Andreas Holger Marx1, Luigi Terracciano2, Uwe Heilenko¨tter3, Fritz Jaenicke4, Carsten Bokemeyer5, Jakob Izbicki6, Guido Sauter1 and Ronald Simon1 1Institute of Pathology, University Medical Centre Hamburg-Eppendorf, Hamburg, Germany; 2Institute of Pathology, University Hospital Basel, Basel, Switzerland; 3Department of Gynaecology, Hospital Itzehoe, Itzehoe, Germany; 4Department of Gynaecology, University Medical Centre Hamburg-Eppendorf, Hamburg, Germany; 5Department of Oncology, Hematology, Bone Marrow Transplantation with Section Pneumology, University Hospital Hamburg-Eppendorf, Hamburg, Germany and 6Department of Surgery, University Medical Centre Hamburg-Eppendorf, Hamburg, Germany Copy number gains involving the long arm of chromosome 8, including high-level amplifications at 8q21 and 8q24, have been frequently reported in breast cancer. Although the role of the MYC gene as the driver of the 8q24 amplicon is well established, the significance of the 8q21 amplicon is less clear. The breast cancer cell line SK-BR-3 contains three separate 8q21 amplicons, the distal two of which correspond to putative target genes TPD52 and WWP1. To understand the effect of proximal 8q21 amplification on breast cancer phenotype and patient prognosis, we analyzed 8q21 copy number changes using fluorescence in situ hybridization (FISH) in a tissue microarray containing more than 2000 breast cancers. Amplification at 8q21 was found in 3% of tumors, and was associated with medullary type (Po0.03), high tumor grade (Po0.0001), high Ki67 labeling index (Po0.05), amplification of MYC (Po0.0001), HER2, MDM2, and CCND1 (Po0.05 each), as well as the total number of gene amplifications (Po0.0001). -
METTL3-Mediated M6a Modification Is Required for Cerebellar Development
RESEARCH ARTICLE METTL3-mediated m6A modification is required for cerebellar development Chen-Xin Wang1,2☯, Guan-Shen Cui3,4☯, Xiuying Liu5☯, Kai Xu1,2☯, Meng Wang5☯, Xin- Xin Zhang1, Li-Yuan Jiang1, Ang Li2,3, Ying Yang3, Wei-Yi Lai2,6, Bao-Fa Sun2,3,7, Gui- Bin Jiang6, Hai-Lin Wang6, Wei-Min Tong8, Wei Li1,2,7, Xiu-Jie Wang2,5,7*, Yun- Gui Yang2,3,7*, Qi Zhou1,2,7* 1 State Key Laboratory of Stem Cell and Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing, China, 2 University of Chinese Academy of Sciences, Beijing, China, 3 Key Laboratory of Genomic and Precision Medicine, Collaborative Innovation Center of Genetics and Development, Beijing a1111111111 Institute of Genomics, Chinese Academy of Sciences, Beijing, China, 4 Sino-Danish College, University of a1111111111 Chinese Academy of Sciences, Beijing, China, 5 Key Laboratory of Genetic Network Biology, Institute of a1111111111 Genetics and Developmental Biology, Chinese Academy of Sciences, Beijing, China, 6 State Key Laboratory a1111111111 of Environmental Chemistry and Ecotoxicology, Research Center for Eco-Environmental Sciences, Chinese a1111111111 Academy of Sciences, Beijing, China, 7 Institute for Stem Cell and Regeneration, Chinese Academy of Sciences, Beijing, China, 8 Department of Pathology, Center for Experimental Animal Research, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China ☯ These authors contributed equally to this work. OPEN ACCESS * [email protected] (XJW); [email protected] (YGY); [email protected] (QZ) Citation: Wang C-X, Cui G-S, Liu X, Xu K, Wang M, Zhang X-X, et al. -
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. -
Epigenome-Wide Exploratory Study of Monozygotic Twins Suggests Differentially Methylated Regions to Associate with Hand Grip Strength
Biogerontology (2019) 20:627–647 https://doi.org/10.1007/s10522-019-09818-1 (0123456789().,-volV)( 0123456789().,-volV) RESEARCH ARTICLE Epigenome-wide exploratory study of monozygotic twins suggests differentially methylated regions to associate with hand grip strength Mette Soerensen . Weilong Li . Birgit Debrabant . Marianne Nygaard . Jonas Mengel-From . Morten Frost . Kaare Christensen . Lene Christiansen . Qihua Tan Received: 15 April 2019 / Accepted: 24 June 2019 / Published online: 28 June 2019 Ó The Author(s) 2019 Abstract Hand grip strength is a measure of mus- significant CpG sites or pathways were found, how- cular strength and is used to study age-related loss of ever two of the suggestive top CpG sites were mapped physical capacity. In order to explore the biological to the COL6A1 and CACNA1B genes, known to be mechanisms that influence hand grip strength varia- related to muscular dysfunction. By investigating tion, an epigenome-wide association study (EWAS) of genomic regions using the comb-p algorithm, several hand grip strength in 672 middle-aged and elderly differentially methylated regions in regulatory monozygotic twins (age 55–90 years) was performed, domains were identified as significantly associated to using both individual and twin pair level analyses, the hand grip strength, and pathway analyses of these latter controlling the influence of genetic variation. regions revealed significant pathways related to the Moreover, as measurements of hand grip strength immune system, autoimmune disorders, including performed over 8 years were available in the elderly diabetes type 1 and viral myocarditis, as well as twins (age 73–90 at intake), a longitudinal EWAS was negative regulation of cell differentiation. -
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. -
'Next- Generation' Sequencing Data Analysis
Novel Algorithm Development for ‘Next- Generation’ Sequencing Data Analysis Agne Antanaviciute Submitted in accordance with the requirements for the degree of Doctor of Philosophy University of Leeds School of Medicine Leeds Institute of Biomedical and Clinical Sciences 12/2017 ii The candidate confirms that the work submitted is her own, except where work which has formed part of jointly-authored publications has been included. The contribution of the candidate and the other authors to this work has been explicitly given within the thesis where reference has been made to the work of others. This copy has been supplied on the understanding that it is copyright material and that no quotation from the thesis may be published without proper acknowledgement ©2017 The University of Leeds and Agne Antanaviciute The right of Agne Antanaviciute to be identified as Author of this work has been asserted by her in accordance with the Copyright, Designs and Patents Act 1988. Acknowledgements I would like to thank all the people who have contributed to this work. First and foremost, my supervisors Dr Ian Carr, Professor David Bonthron and Dr Christopher Watson, who have provided guidance, support and motivation. I could not have asked for a better supervisory team. I would also like to thank my collaborators Dr Belinda Baquero and Professor Adrian Whitehouse for opening new, interesting research avenues. A special thanks to Dr Belinda Baquero for all the hard wet lab work without which at least half of this thesis would not exist. Thanks to everyone at the NGS Facility – Carolina Lascelles, Catherine Daley, Sally Harrison, Ummey Hany and Laura Crinnion – for the generation of NGS data used in this work and creating a supportive and stimulating work environment. -
MYC-Containing Amplicons in Acute Myeloid Leukemia: Genomic Structures, Evolution, and Transcriptional Consequences
Leukemia (2018) 32:2152–2166 https://doi.org/10.1038/s41375-018-0033-0 ARTICLE Acute myeloid leukemia Corrected: Correction MYC-containing amplicons in acute myeloid leukemia: genomic structures, evolution, and transcriptional consequences 1 1 2 2 1 Alberto L’Abbate ● Doron Tolomeo ● Ingrid Cifola ● Marco Severgnini ● Antonella Turchiano ● 3 3 1 1 1 Bartolomeo Augello ● Gabriella Squeo ● Pietro D’Addabbo ● Debora Traversa ● Giulia Daniele ● 1 1 3 3 4 Angelo Lonoce ● Mariella Pafundi ● Massimo Carella ● Orazio Palumbo ● Anna Dolnik ● 5 5 6 2 7 Dominique Muehlematter ● Jacqueline Schoumans ● Nadine Van Roy ● Gianluca De Bellis ● Giovanni Martinelli ● 3 4 8 1 Giuseppe Merla ● Lars Bullinger ● Claudia Haferlach ● Clelia Tiziana Storlazzi Received: 4 August 2017 / Revised: 27 October 2017 / Accepted: 13 November 2017 / Published online: 22 February 2018 © The Author(s) 2018. This article is published with open access Abstract Double minutes (dmin), homogeneously staining regions, and ring chromosomes are vehicles of gene amplification in cancer. The underlying mechanism leading to their formation as well as their structure and function in acute myeloid leukemia (AML) remain mysterious. We combined a range of high-resolution genomic methods to investigate the architecture and expression pattern of amplicons involving chromosome band 8q24 in 23 cases of AML (AML-amp). This 1234567890();,: revealed that different MYC-dmin architectures can coexist within the same leukemic cell population, indicating a step-wise evolution rather than a single event origin, such as through chromothripsis. This was supported also by the analysis of the chromothripsis criteria, that poorly matched the model in our samples. Furthermore, we found that dmin could evolve toward ring chromosomes stabilized by neocentromeres. -
Large-Scale Functional Prediction of Individual M6a RNA Methylation Sites from an RNA Co-Methylation Network
Wu et al. BMC Bioinformatics (2019) 20:223 https://doi.org/10.1186/s12859-019-2840-3 RESEARCHARTICLE Open Access m6Acomet: large-scale functional prediction of individual m6A RNA methylation sites from an RNA co- methylation network Xiangyu Wu1,2, Zhen Wei1,2, Kunqi Chen1,2, Qing Zhang1,4, Jionglong Su5, Hui Liu6, Lin Zhang6* and Jia Meng1,3* Abstract Background: Over one hundred different types of post-transcriptional RNA modifications have been identified in human. Researchers discovered that RNA modifications can regulate various biological processes, and RNA methylation, especially N6-methyladenosine, has become one of the most researched topics in epigenetics. Results: To date, the study of epitranscriptome layer gene regulation is mostly focused on the function of mediator proteins of RNA methylation, i.e., the readers, writers and erasers. There is limited investigation of the functional relevance of individual m6A RNA methylation site. To address this, we annotated human m6A sites in large-scale based on the guilt-by-association principle from an RNA co-methylation network. It is constructed based on public human MeRIP-Seq datasets profiling the m6A epitranscriptome under 32 independent experimental conditions. By systematically examining the network characteristics obtained from the RNA methylation profiles, a total of 339,158 putative gene ontology functions associated with 1446 human m6A sites were identified. These are biological functions that may be regulated at epitranscriptome layer via reversible m6A RNA methylation. The results were further validated on a soft benchmark by comparing to a random predictor. Conclusions: An online web server m6Acomet was constructed to support direct query for the predicted biological functions of m6A sites as well as the sites exhibiting co-methylated patterns at the epitranscriptome layer. -
Exploring the Human Protein Atlas (HPA) Portal for New Biomarkers in Urinary Bladder Carcinoma
Exploring the Human Protein Atlas (HPA) Portal for New Biomarkers in Urinary Bladder Carcinoma Tina Bergström Bachelor degree project in biomedicine, 10 hp, 2010 Department of Genetics and Pathology, Uppsala University Supervisors: Ulrika Segersten and Kenneth Wester Summary Urinary bladder cancer is the fifth most common cancer form in industrial countries. The primary risk factors for bladder cancer are tobacco smoking, exposure to aromatic amines from occupational sources, cancer drugs and Schistosomal infection. Vegetables, fruit and a high intake of fluid are considered as risk reducing factors for developing bladder cancer. Diagnosis and management of bladder cancer includes cystoscopy, an invasive method causing patients pain and discomfort. Hence, there is great need for non-invasive methods, such as biomarkers predicting tumour recurrence or progression. The aim of this study was to finding new potential biomarkers for urinary bladder carcinoma by exploration of the Human Protein Atlas (HPA) database portal, an antibody-based protein atlas comprising histological images which are a resource for many areas of biomedical research, including biomarker discovery. Initially, 35 selected proteins were evaluated in 42 tissue scores, representing bladder cancer biopsies from 24 individual cancer patients of which 7 had low-grade and 17 had high-grade tumours. The protein expression in tumour cells was scored and related to high and low tumour grade. Expression pattern for two proteins, 4, also known as immunoglobulin binding protein 1 (IGBP1) and UPF0500 protein C1orf216, were significantly altered (p < 0.5) with tumour grades. The function of C1orf216 is so far unknown. 4 is a regulator of protein phosphatase 2 (PP2A) and thereby controls dephosphorylation of substrates important in cell survival, apoptosis and cell migration. -
Promoter-Bound METTL3 Maintains Myeloid Leukaemia Via M6a-Dependent Translation Control
1 2 Promoter-bound METTL3 maintains myeloid leukaemia 3 via m6A-dependent translation control 4 5 6 Isaia Barbieri1*, Konstantinos Tzelepis2*, Luca Pandolfini1*, Junwei Shi3♯, Gonzalo Millán- 7 Zambrano1, Samuel C. Robson1¶, Demetrios Aspris2, Valentina Migliori1, Andrew J. 8 Bannister1, Namshik Han1, Etienne De Braekeleer2, Hannes Ponstingl2, Alan Hendrick4, 9 Christopher R. Vakoc3, George S. Vassiliou2§ & Tony Kouzarides1§. 10 11 1The Gurdon Institute and Department of Pathology, University of Cambridge, Tennis Court Road, 12 Cambridge, CB2 1QN, UK. 13 2 Haematological Cancer Genetics, Wellcome Trust Sanger Institute, Cambridge, CB10 1SA, UK. 14 3 Cold Spring Harbor Laboratory, 1 Bungtown Road, Cold Spring Harbor, NY 11724, USA. 15 4 Storm Therapeutics Ltd, Moneta building (B280), Babraham Research Campus, Cambridge CB22 3AT, UK. 16 17 ♯ Present address: Department of Cancer Biology, Abramson Family Cancer Research Institute, Perelman 18 School of Medicine, University of Pennsylvania, 421 Curie Boulevard, Philadelphia, Pennsylvania 19104, 19 USA. 20 ¶Present address: School of Pharmacy & Biomedical Science, St Michael's Building, University of 21 Portsmouth, White Swan Road, Portsmouth, UK" 22 *These authors contributed equally to the work. 23 §Corresponding authors ([email protected]; [email protected]) 24 25 26 27 Abstract 28 29 N6-methyladenosine (m6A) is an abundant internal RNA modification in both coding1 and 30 non-coding RNAs2,3, catalysed by the METTL3/METTL14 methyltransferase complex4. 31 Here we define a novel pathway specific for METTL3, implicated in the maintenance of the 32 leukaemic state. We identify METTL3 as an essential gene for growth of acute myeloid 33 leukaemia (AML) cells in two distinct genetic screens. -
B01P) Gene Alias: IME4, M6A, MGC4336, MT-A70, Spo8
METTL3 purified MaxPab mouse Gene Symbol: METTL3 polyclonal antibody (B01P) Gene Alias: IME4, M6A, MGC4336, MT-A70, Spo8 Catalog Number: H00056339-B01P Gene Summary: This gene encodes the 70 kDa subunit of MT-A which is part of Regulatory Status: For research use only (RUO) N6-adenosine-methyltransferase. This enzyme is involved in the posttranscriptional methylation of internal Product Description: Mouse polyclonal antibody raised adenosine residues in eukaryotic mRNAs, forming against a full-length human METTL3 protein. N6-methyladenosine. [provided by RefSeq] Immunogen: METTL3 (NP_062826.2, 1 a.a. ~ 580 a.a) References: full-length human protein. 1. Synaptic N6-methyladenosine (m6A) epitranscriptome Sequence: reveals functional partitioning of localized transcripts. MSDTWSSIQAHKKQLDSLRERLQRRRKQDSGHLDLR Merkurjev D, Hong WT, Iida K, Oomoto I, Goldie BJ, NPEAALSPTFRSDSPVPTAPTSGGPKPSTASAVPELAT Yamaguti H, Ohara T, Kawaguchi SY, Hirano T, Martin DPELEKKLLHHLSDLALTLPTDAVSICLAISTPDAPATQ KC, Pellegrini M, Wang DO. Nat Neurosci. 2018 DGVESLLQKFAAQELIEVKRGLLQDDAHPTLVTYADHS Jul;21(7):1004-1014. doi: 10.1038/s41593-018-0173-6. KLSAMMGAVAEKKGPGEVAGTVTGQKRRAEQDSTTV Epub 2018 Jun 27. AAFASSLVSGLNSSASEPAKEPAKKSRKHAASDVDLEI 2. The RNA Methyltransferase Complex of WTAP, ESLLNQQSTKEQQSKKVSQEILELLNTTTAKEQSIVEKF METTL3, and METTL14 Regulates Mitotic Clonal RSRGRAQVQEFCDYGTKEECMKASDADRPCRKLHFR Expansion in Adipogenesis. Kobayashi M, Ohsugi M, RIINKHTDESLGDCSFLNTCFHMDTCKYVHYEIDACMD Sasako T, Awazawa M, Umehara T, Iwane A, Kobayashi SEAPGSKDHTPSQELALTQSVGGDSSADRLFPPQWIC -
Human Induced Pluripotent Stem Cell–Derived Podocytes Mature Into Vascularized Glomeruli Upon Experimental Transplantation
BASIC RESEARCH www.jasn.org Human Induced Pluripotent Stem Cell–Derived Podocytes Mature into Vascularized Glomeruli upon Experimental Transplantation † Sazia Sharmin,* Atsuhiro Taguchi,* Yusuke Kaku,* Yasuhiro Yoshimura,* Tomoko Ohmori,* ‡ † ‡ Tetsushi Sakuma, Masashi Mukoyama, Takashi Yamamoto, Hidetake Kurihara,§ and | Ryuichi Nishinakamura* *Department of Kidney Development, Institute of Molecular Embryology and Genetics, and †Department of Nephrology, Faculty of Life Sciences, Kumamoto University, Kumamoto, Japan; ‡Department of Mathematical and Life Sciences, Graduate School of Science, Hiroshima University, Hiroshima, Japan; §Division of Anatomy, Juntendo University School of Medicine, Tokyo, Japan; and |Japan Science and Technology Agency, CREST, Kumamoto, Japan ABSTRACT Glomerular podocytes express proteins, such as nephrin, that constitute the slit diaphragm, thereby contributing to the filtration process in the kidney. Glomerular development has been analyzed mainly in mice, whereas analysis of human kidney development has been minimal because of limited access to embryonic kidneys. We previously reported the induction of three-dimensional primordial glomeruli from human induced pluripotent stem (iPS) cells. Here, using transcription activator–like effector nuclease-mediated homologous recombination, we generated human iPS cell lines that express green fluorescent protein (GFP) in the NPHS1 locus, which encodes nephrin, and we show that GFP expression facilitated accurate visualization of nephrin-positive podocyte formation in