Identification of a Novel Set of Genes Reflecting Different in Vivo Invasive
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Molecular and Physiological Basis for Hair Loss in Near Naked Hairless and Oak Ridge Rhino-Like Mouse Models: Tracking the Role of the Hairless Gene
University of Tennessee, Knoxville TRACE: Tennessee Research and Creative Exchange Doctoral Dissertations Graduate School 5-2006 Molecular and Physiological Basis for Hair Loss in Near Naked Hairless and Oak Ridge Rhino-like Mouse Models: Tracking the Role of the Hairless Gene Yutao Liu University of Tennessee - Knoxville Follow this and additional works at: https://trace.tennessee.edu/utk_graddiss Part of the Life Sciences Commons Recommended Citation Liu, Yutao, "Molecular and Physiological Basis for Hair Loss in Near Naked Hairless and Oak Ridge Rhino- like Mouse Models: Tracking the Role of the Hairless Gene. " PhD diss., University of Tennessee, 2006. https://trace.tennessee.edu/utk_graddiss/1824 This Dissertation is brought to you for free and open access by the Graduate School at TRACE: Tennessee Research and Creative Exchange. It has been accepted for inclusion in Doctoral Dissertations by an authorized administrator of TRACE: Tennessee Research and Creative Exchange. For more information, please contact [email protected]. To the Graduate Council: I am submitting herewith a dissertation written by Yutao Liu entitled "Molecular and Physiological Basis for Hair Loss in Near Naked Hairless and Oak Ridge Rhino-like Mouse Models: Tracking the Role of the Hairless Gene." I have examined the final electronic copy of this dissertation for form and content and recommend that it be accepted in partial fulfillment of the requirements for the degree of Doctor of Philosophy, with a major in Life Sciences. Brynn H. Voy, Major Professor We have read this dissertation and recommend its acceptance: Naima Moustaid-Moussa, Yisong Wang, Rogert Hettich Accepted for the Council: Carolyn R. -
Ageing-Associated Changes in DNA Methylation in X and Y Chromosomes
Kananen and Marttila Epigenetics & Chromatin (2021) 14:33 Epigenetics & Chromatin https://doi.org/10.1186/s13072-021-00407-6 RESEARCH Open Access Ageing-associated changes in DNA methylation in X and Y chromosomes Laura Kananen1,2,3,4* and Saara Marttila4,5* Abstract Background: Ageing displays clear sexual dimorphism, evident in both morbidity and mortality. Ageing is also asso- ciated with changes in DNA methylation, but very little focus has been on the sex chromosomes, potential biological contributors to the observed sexual dimorphism. Here, we sought to identify DNA methylation changes associated with ageing in the Y and X chromosomes, by utilizing datasets available in data repositories, comprising in total of 1240 males and 1191 females, aged 14–92 years. Results: In total, we identifed 46 age-associated CpG sites in the male Y, 1327 age-associated CpG sites in the male X, and 325 age-associated CpG sites in the female X. The X chromosomal age-associated CpGs showed signifcant overlap between females and males, with 122 CpGs identifed as age-associated in both sexes. Age-associated X chro- mosomal CpGs in both sexes were enriched in CpG islands and depleted from gene bodies and showed no strong trend towards hypermethylation nor hypomethylation. In contrast, the Y chromosomal age-associated CpGs were enriched in gene bodies, and showed a clear trend towards hypermethylation with age. Conclusions: Signifcant overlap in X chromosomal age-associated CpGs identifed in males and females and their shared features suggest that despite the uneven chromosomal dosage, diferences in ageing-associated DNA methylation changes in the X chromosome are unlikely to be a major contributor of sex dimorphism in ageing. -
Supplementary Table 1: Adhesion Genes Data Set
Supplementary Table 1: Adhesion genes data set PROBE Entrez Gene ID Celera Gene ID Gene_Symbol Gene_Name 160832 1 hCG201364.3 A1BG alpha-1-B glycoprotein 223658 1 hCG201364.3 A1BG alpha-1-B glycoprotein 212988 102 hCG40040.3 ADAM10 ADAM metallopeptidase domain 10 133411 4185 hCG28232.2 ADAM11 ADAM metallopeptidase domain 11 110695 8038 hCG40937.4 ADAM12 ADAM metallopeptidase domain 12 (meltrin alpha) 195222 8038 hCG40937.4 ADAM12 ADAM metallopeptidase domain 12 (meltrin alpha) 165344 8751 hCG20021.3 ADAM15 ADAM metallopeptidase domain 15 (metargidin) 189065 6868 null ADAM17 ADAM metallopeptidase domain 17 (tumor necrosis factor, alpha, converting enzyme) 108119 8728 hCG15398.4 ADAM19 ADAM metallopeptidase domain 19 (meltrin beta) 117763 8748 hCG20675.3 ADAM20 ADAM metallopeptidase domain 20 126448 8747 hCG1785634.2 ADAM21 ADAM metallopeptidase domain 21 208981 8747 hCG1785634.2|hCG2042897 ADAM21 ADAM metallopeptidase domain 21 180903 53616 hCG17212.4 ADAM22 ADAM metallopeptidase domain 22 177272 8745 hCG1811623.1 ADAM23 ADAM metallopeptidase domain 23 102384 10863 hCG1818505.1 ADAM28 ADAM metallopeptidase domain 28 119968 11086 hCG1786734.2 ADAM29 ADAM metallopeptidase domain 29 205542 11085 hCG1997196.1 ADAM30 ADAM metallopeptidase domain 30 148417 80332 hCG39255.4 ADAM33 ADAM metallopeptidase domain 33 140492 8756 hCG1789002.2 ADAM7 ADAM metallopeptidase domain 7 122603 101 hCG1816947.1 ADAM8 ADAM metallopeptidase domain 8 183965 8754 hCG1996391 ADAM9 ADAM metallopeptidase domain 9 (meltrin gamma) 129974 27299 hCG15447.3 ADAMDEC1 ADAM-like, -
Learning from Cadherin Structures and Sequences: Affinity Determinants and Protein Architecture
Learning from cadherin structures and sequences: affinity determinants and protein architecture Klára Fels ıvályi Submitted in partial fulfillment of the requirements for the degree of Doctor of Philosophy in the Graduate School of Arts and Sciences COLUMBIA UNIVERSITY 2014 © 2014 Klara Felsovalyi All rights reserved ABSTRACT Learning from cadherin structures and sequences: affinity determinants and protein architecture Klara Felsovalyi Cadherins are a family of cell-surface proteins mediating adhesion that are important in development and maintenance of tissues. The family is defined by the repeating cadherin domain (EC) in their extracellular region, but they are diverse in terms of protein size, architecture and cellular function. The best-understood subfamily is the type I classical cadherins, which are found in vertebrates and have five EC domains. Among the five different type I classical cadherins, the binding interactions are highly specific in their homo- and heterophilic binding affinities, though their sequences are very similar. As previously shown, E- and N-cadherins, two prototypic members of the subfamily, differ in their homophilic K D by about an order of magnitude, while their heterophilic affinity is intermediate. To examine the source of the binding affinity differences among type I cadherins, we used crystal structures, analytical ultracentrifugation (AUC), surface plasmon resonance (SPR), and electron paramagnetic resonance (EPR) studies. Phylogenetic analysis and binding affinity behavior show that the type I cadherins can be further divided into two subgroups, with E- and N-cadherin representing each. In addition to the affinity differences in their wild-type binding through the strand-swapped interface, a second interface also shows an affinity difference between E- and N-cadherin. -
Acceleration in the DNA Methylation Age in Breast Cancer Tumours from Very Young Women Sara S
www.nature.com/scientificreports OPEN Acceleration in the DNA methylation age in breast cancer tumours from very young women Sara S. Oltra1, Maria Peña-Chilet1, Kirsty Flower2, María Teresa Martinez1, Elisa Alonso3, Octavio Burgues3, Ana Lluch1,4, James M. Flanagan 2 & Gloria Ribas1,4* Breast cancer in very young women (≤35 years; BCVY) presents more aggressive and complex biological features than their older counterparts (BCO). Our aim was to evaluate methylation diferences between BCVY and BCO and their DNA epigenetic age. EPIC and 450k Illumina methylation arrays were used in 67 breast cancer tumours, including 32 from BCVY, for methylation study and additionally we analysed their epigenetic age. We identifed 2 219 CpG sites diferently-methylated in BCVY vs. BCO (FDR < 0.05; β-value diference ± 0.1). The signature showed a general hypomethylation profle with a selective small hypermethylation profle located in open-sea regions in BCVY against BCO and normal tissue. Strikingly, BCVY presented a signifcant increased epigenetic age-acceleration compared with older women. The afected genes were enriched for pathways in neuronal-system pathways, cell communication, and matrix organisation. Validation in an independent sample highlighted consistent higher expression of HOXD9, and PCDH10 genes in BCVY. Regions implicated in the hypermethylation profle were involved in Notch signalling pathways, the immune system or DNA repair. We further validated HDAC5 expression in BCVY. We have identifed a DNA methylation signature that is specifc to BCVY and have shown that epigenetic age-acceleration is increased in BCVY. Breast cancer (BC) is the most common malignancy in women worldwide1. Approximately 6.6% of BCs are diag- nosed in women aged 40 or younger, and of all cancers diagnosed in this age group, 40% are BCs; the average risk of developing BC by age 40 is one in 1732 and unfortunately, they are not included in mammography screening programmes. -
Slitrks Control Excitatory and Inhibitory Synapse Formation with LAR
Slitrks control excitatory and inhibitory synapse SEE COMMENTARY formation with LAR receptor protein tyrosine phosphatases Yeong Shin Yima,1, Younghee Kwonb,1, Jungyong Namc, Hong In Yoona, Kangduk Leeb, Dong Goo Kima, Eunjoon Kimc, Chul Hoon Kima,2, and Jaewon Kob,2 aDepartment of Pharmacology, Brain Research Institute, Brain Korea 21 Project for Medical Science, Severance Biomedical Science Institute, Yonsei University College of Medicine, Seoul 120-752, Korea; bDepartment of Biochemistry, College of Life Science and Biotechnology, Yonsei University, Seoul 120-749, Korea; and cCenter for Synaptic Brain Dysfunctions, Institute for Basic Science, Department of Biological Sciences, Korea Advanced Institute of Science and Technology, Daejeon 305-701, Korea Edited by Thomas C. Südhof, Stanford University School of Medicine, Stanford, CA, and approved December 26, 2012 (received for review June 11, 2012) The balance between excitatory and inhibitory synaptic inputs, share a similar domain organization comprising three Ig domains which is governed by multiple synapse organizers, controls neural and four to eight fibronectin type III repeats. LAR-RPTP family circuit functions and behaviors. Slit- and Trk-like proteins (Slitrks) are members are evolutionarily conserved and are functionally required a family of synapse organizers, whose emerging synaptic roles are for axon guidance and synapse formation (15). Recent studies have incompletely understood. Here, we report that Slitrks are enriched shown that netrin-G ligand-3 (NGL-3), neurotrophin receptor ty- in postsynaptic densities in rat brains. Overexpression of Slitrks rosine kinase C (TrkC), and IL-1 receptor accessory protein-like 1 promoted synapse formation, whereas RNAi-mediated knock- (IL1RAPL1) bind to all three LAR-RPTP family members or dis- down of Slitrks decreased synapse density. -
Slitrk1 Is Localized to Excitatory Synapses and Promotes Their Development Received: 30 July 2015 François Beaubien1,2,*, Reesha Raja1,2,*, Timothy E
www.nature.com/scientificreports OPEN Slitrk1 is localized to excitatory synapses and promotes their development Received: 30 July 2015 François Beaubien1,2,*, Reesha Raja1,2,*, Timothy E. Kennedy1,3, Alyson E. Fournier1,3 & Accepted: 09 May 2016 Jean-François Cloutier1,3 Published: 07 June 2016 Following the migration of the axonal growth cone to its target area, the initial axo-dendritic contact needs to be transformed into a functional synapse. This multi-step process relies on overlapping but distinct combinations of molecules that confer synaptic identity. Slitrk molecules are transmembrane proteins that are highly expressed in the central nervous system. We found that two members of the Slitrk family, Slitrk1 and Slitrk2, can regulate synapse formation between hippocampal neurons. Slitrk1 is enriched in postsynaptic fractions and is localized to excitatory synapses. Overexpression of Slitrk1 and Slitrk2 in hippocampal neurons increased the number of synaptic contacts on these neurons. Furthermore, decreased expression of Slitrk1 in hippocampal neurons led to a reduction in the number of excitatory, but not inhibitory, synapses formed in hippocampal neuron cultures. In addition, we demonstrate that different leucine rich repeat domains of the extracellular region of Slitrk1 are necessary to mediate interactions with Slitrk binding partners of the LAR receptor protein tyrosine phosphatase family, and to promote dimerization of Slitrk1. Altogether, our results demonstrate that Slitrk family proteins regulate synapse formation. One of the key steps in the development of the nervous system is the formation of new connections between different neurons. This process, referred to as synaptogenesis, also plays a critical role in the mature brain where the dynamic modification of circuitry has a profound effect on functions such as learning and memory. -
Detection of Somatic Variants from Genomic Data and Their Role in Neurodegenerative Diseases
Detection of somatic variants from genomic data and their role in neurodegenerative diseases Irene Lobón García Aquesta tesi doctoral està subjecta a la llicència Reconeixement 4.0. Espanya de Creative Commons. Esta tesis doctoral está sujeta a la licencia Reconocimiento 4.0. España de Creative Commons. This doctoral thesis is licensed under the Creative Commons Attribution 4.0. Spain License. Memoria presentada por Irene Lobón García para optar al grado de doctora por la Universidad de Barcelona Programa de Doctorado en Biomedicina Tesis realizada en el Instituto de Biología Evolutiva (CSIC-UPF) Detection oF somatic variants From genomic data and their role in neurodegenerative diseases Irene Lobón García Eduardo Soriano García Tomàs Marquès Bonet A mi Familia, “La paciencia es la madre de la ciencia” ReFranero español Acknowledgements De estos cinco años me llevo innumerables enseñanzas. Por supuesto muchas en lo profesional, pero incluso más en lo personal. Esta tesis ha sido un trabajo en grupo y sin el apoyo y ayuda de mucha gente hubiese sido imposible. En primer lugar, quiero agradecer a Eduardo su conFianza todos estos años y sobre todo el haberme introducido con sus proyectos en el tema que ahora me apasiona. También a Tomàs por aceptarme en su grupo como estudiante de máster y después hacer lo posible para que me quedase de alguna manera en el grupo. También por introducirme en el consorcio que ha sido fundamental para mi trabajo y porque nunca hubiese salido de mí pedir una estancia en Harvard. Esta experiencia solo ha sido posible gracias a vosotros. Los comienzos Fueron duros, después de tantos años de aprendizaje guiado el salto a la investigación es diFícil. -
Discovery of an O-Mannosylation Pathway Selectively Serving Cadherins and Protocadherins
Discovery of an O-mannosylation pathway selectively serving cadherins and protocadherins Ida Signe Bohse Larsena,1, Yoshiki Narimatsua,1, Hiren Jitendra Joshia,1, Lina Siukstaitea, Oliver J. Harrisonb, Julia Braschb, Kerry M. Goodmanb, Lars Hansena, Lawrence Shapirob,c,d, Barry Honigb,c,d,e, Sergey Y. Vakhrusheva, Henrik Clausena, and Adnan Halima,2,3 aDepartment of Cellular and Molecular Medicine, Faculty of Health Sciences, Copenhagen Center for Glycomics, University of Copenhagen, DK-2200 Copenhagen, Denmark; bDepartment of Biochemistry and Molecular Biophysics, Columbia University, New York, NY 10032; cZuckerman Mind Brain Behavior Institute, Columbia University, New York, NY 10032; dDepartment of Systems Biology, Columbia University, New York, NY 10032; and eHoward Hughes Medical Institute, Columbia University, New York, NY 10032 Edited by Stuart A. Kornfeld, Washington University School of Medicine, St. Louis, MO, and approved September 6, 2017 (received for review May 22, 2017) The cadherin (cdh) superfamily of adhesion molecules carry muscular dystrophies that have been designated α-dystroglyca- O-linked mannose (O-Man) glycans at highly conserved sites nopathies because deficient O-Man glycosylation of α-DG dis- localized to specific β-strands of their extracellular cdh (EC) domains. rupts the interaction between the dystrophin glycoprotein complex These O-Man glycans do not appear to be elongated like O-Man and the ECM (7–9). Several studies have also implicated de- glycans found on α-dystroglycan (α-DG), and we recently demon- ficiency of POMT2 with E-cdh dysfunction (10–12), although di- strated that initiation of cdh/protocadherin (pcdh) O-Man glycosyl- rect evidence for a role in glycosylation of cdhs and pcdhs is ation is not dependent on the evolutionary conserved POMT1/ missing. -
A Protocol for Constructing Gene Targeting Vectors: Generating Knockout Mice for the Cadherin Family and Beyond
PROTOCOL A protocol for constructing gene targeting vectors: generating knockout mice for the cadherin family and beyond Sen Wu1, Guoxin Ying2, Qiang Wu2 & Mario R Capecchi1,2 1Howard Hughes Medical Institute and 2Department of Human Genetics, University of Utah, Salt Lake City, Utah 84112, USA. Correspondence should be addressed to M.R.C. ([email protected]). Published online 29 May 2008; doi:10.1038/nprot.2008.70 s We describe here a streamlined procedure for targeting vector construction, which often is a limiting factor for gene targeting (knockout) technology. This procedure combines various highly efficient recombination-based cloning methods in bacteria, consisting of three steps. First step is the use of Red-pathway-mediated recombination (recombineering) to capture a genomic fragment into a Gateway-compatible vector. Second, the vector is modified by recombineering to include a positive selection gene neo,fromavariety natureprotocol / of modular reagents. Finally, through a simple in vitro Gateway recombination, the modified genomic fragment is switched into a m o c vector that contains negative selection cassettes, as well as unique sites for linearization. To demonstrate the usefulness of this . e r protocol, we report targeted disruptions of members of the cadherin gene family, focusing on those that have not been previously u t B a studied at the molecular genetic level. This protocol needs 2 weeks to construct a targeting vector, and several vectors can be n . easily handled simultaneously using common laboratory setup. w w w / / : p t INTRODUCTION t h Gene targeting, the use of homologous recombination in mouse this procedure is reduced when used for generating large DNA p 1–5 19,20 u embryonic stem (ES) cells to modify mouse genes precisely , constructs, required for gene targeting vector construction . -
Effect of Single-Nucleotide Polymorphisms on Specific Reproduction Parameters in Hungarian Large White Sows
Acta Veterinaria Hungarica 67 (2), pp. 256–273 (2019) DOI: 10.1556/004.2019.027 EFFECT OF SINGLE-NUCLEOTIDE POLYMORPHISMS ON SPECIFIC REPRODUCTION PARAMETERS IN HUNGARIAN LARGE WHITE SOWS 1 1 1 1 2 Eszter Erika BALOGH , György GÁBOR , Szilárd BODÓ , László RÓZSA , József RÁTKY , 1* 1 Attila ZSOLNAI and István ANTON 1NARIC Research Institute for Animal Breeding, Nutrition and Meat Science, Gesztenyés u. 1, H-2053 Herceghalom, Hungary; 2Department of Obstetrics and Reproduction, University of Veterinary Medicine, Budapest, Hungary (Received 21 January 2019; accepted 2 May 2019) The aim of this study was to reveal the effect of single-nucleotide poly- morphisms (SNPs) on the total number of piglets born (TNB), the litter weight born alive (LWA), the number of piglets born dead (NBD), the average litter weight on the 21st day (M21D) and the interval between litters (IBL). Genotypes were determined on a high-density Illumina Porcine SNP 60K BeadChip. Data screening and data identification were performed by a multi-locus mixed-model. Statistical analyses were carried out to find associations between individual geno- types of 290 Hungarian Large White sows and the investigated reproduction pa- rameters. According to the analysis outcome, three SNPs were identified to be as- sociated with TNB. These loci are located on chromosomes 1, 6 and 13 (–log10P = 6.0, 7.86 and 6.22, the frequencies of their minor alleles, MAF, were 0.298, 0.299 and 0.364, respectively). Two loci showed considerable association (–log10P = 10.35 and 10.46) with LWA on chromosomes 5 and X, the MAF were 0.425 and 0.446, respectively. -
Retrospective Evaluation of Whole Exome and Genome Mutation Calls in 746 Cancer Samples
ARTICLE https://doi.org/10.1038/s41467-020-18151-y OPEN Retrospective evaluation of whole exome and genome mutation calls in 746 cancer samples Matthew H. Bailey 1,2,3, William U. Meyerson4,5, Lewis Jonathan Dursi 6,7, Liang-Bo Wang 1,2, Guanlan Dong 2, Wen-Wei Liang1,2, Amila Weerasinghe 1,2, Shantao Li 5, Sean Kelso2, MC3 Working Group*, PCAWG novel somatic mutation calling methods working group*, Gordon Saksena 8, Kyle Ellrott 9, Michael C. Wendl1,10,11, David A. Wheeler 12,13, Gad Getz 8,14,15,16, Jared T. Simpson6,17, ✉ ✉ Mark B. Gerstein 5,18,19 , Li Ding1,2,3,20 & PCAWG Consortium* 1234567890():,; The Cancer Genome Atlas (TCGA) and International Cancer Genome Consortium (ICGC) curated consensus somatic mutation calls using whole exome sequencing (WES) and whole genome sequencing (WGS), respectively. Here, as part of the ICGC/TCGA Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium, which aggregated whole genome sequencing data from 2,658 cancers across 38 tumour types, we compare WES and WGS side-by-side from 746 TCGA samples, finding that ~80% of mutations overlap in covered exonic regions. We estimate that low variant allele fraction (VAF < 15%) and clonal het- erogeneity contribute up to 68% of private WGS mutations and 71% of private WES mutations. We observe that ~30% of private WGS mutations trace to mutations identified by a single variant caller in WES consensus efforts. WGS captures both ~50% more variation in exonic regions and un-observed mutations in loci with variable GC-content. Together, our analysis highlights technological divergences between two reproducible somatic variant detection efforts.