DOCSLIB.ORG

X-Chromosome Inactivation

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text

Load more

Autosomal random asynchronous replication is analogous to X-chromosome inactivation By MAS HUSETTS INSTITUTEI Alexander Wilson Ensminger OF TECHNOLOGY B.S. Biology FEB 1 2006 Haverford College Haverford, PA 19041 LIBRARIES Submitted to the Department of Biology in Partial Fulfillment of the Requirements for the Degree of Doctor of Philosophy in Biology at the 4*'CHIVES Massachusetts Institute of Technology February, 2006 © 2005 Alexander W. Ensminger. All rights reserved. The author hereby grants to MIT permission to reproduce and to distribute publicly paper and electronic copies of this thesis document in whole or in part in any medium now known or hereafter created. Signature of A uthor .......... r........................... ..... Department of Biology October 28, 2005 Certified by.. .......................... Andrew Chess Associate Professor of Biology Thesis Supervisor A ccepted by ..............................------ ..................................... Stephen P. Bell Chair, Committee on Graduate Students Department of Biology Autosomal random asynchronous replication is analogous to X-chromosome inactivation by Alexander Wilson Ensminger Submitted to the Department of Biology on October 28, 2005 in Partial Fulfillment of the Requirements for the Degree of Doctor of Philosophy in Biology Abstract A number of mammalian genes are expressed from only one of two alleles in either an imprinted or random manner. Those belonging to the random class include X-linked genes subject to X inactivation, as well as a number of autosomal genes, including odorant receptors, immunoglobulins, T-cell receptors, interleukins, natural killer-cell receptors, and pheromone receptors. Random asynchronous replication of DNA in S-phase represents an epigenetic mark that often parallels monoallelic expression. All randomly monoallelically expressed genes discovered to date replicate asynchronously in S-phase, though not all of the genes contained within asynchronous domains are monoallelically expressed. The focus of my work has been on understanding this random choice that cells make between two sequence-identical alleles. Using two-color fluorescent in situ hybridization (FISH) analyses, the random asynchronous replication of a large number of human and mouse genes appears to be coordinated at the level of entire chromosomes. This regulatory scheme is reminiscent of random X-chromosome inactivation, the dosage compensation machinery in mammals. We have shown that autosomal coordination responds to trisomy in a fashion similar to X inactivation, with one copy of the trisomic chromosome marked for early replication and the other two rendered late replicating. These observations raise the intriguing possibility that the mechanistic underpinnings of X inactivation and autosomal coordination may also be similar. Furthermore, the existence of chromosome- wide epigenetic differentiation between autosomes has evolutionary implications concerning the establishment of X inactivation as the approach to mammalian dosage compensation. A crucial event in X inactivation is the random monoallelic expression of a noncoding RNA, Xist from one of the two X chromosomes. Noncoding RNA transcripts are enticing candidates for regulating chromatin structure within the mammalian nucleus. We have initiated a screen for novel nuclear, noncoding RNA transcripts. Using expression array profiling, we have identified several broadly expressed nuclear enriched transcripts. In addition to Xist, this approach identified two noncoding transcripts, NEATI and NEAT2 that are located near one another on human chromosome 1I and chromosome 19 of mice. Using a variety of techniques, including RNA FISH and RNA-mediated interference, we have explored the potential regulatory functions of these transcripts. Thesis Supervisor: Andrew Chess Title: Associate Professor of Biology 2 Dedicated to Julie Claycomb and William and Karen Ensminger 3 Acknowledgements There are a number of people who have contributed to my progress as a student over the years and have helped me to find this path. I have always felt that things work out ok if you just wait long enough. Graduate school has certainly had its share of challenges, both personal and professional. The ability to look at the opportunities afforded by temporary defeat and to keep things in perspective has been indispensable. The feeling that everything is going to be okay if you just stick it out is probably part genetic and part environment. Surely, that level of optimism is reinforced if things really do turn out okay in the end. I want to thank my parents for not only instilling that belief, but also for being there to make sure that it comes true. I certainly have had my share of ups and downs over the past several years, but they were there in the peaks and the valleys, helping to keep things in perspective. I feel very lucky to be their son. One of the major peaks for me during graduate school was the development of some great friendships over these years. One of these friendships, with my wife, Julie Claycomb, deserves particular highlighting. We started out as classmates in 7.50. Years passed (as they often do in grad school) and we became good friends. It is a remarkable experience to have such a partner in every facet of life. We have helped each other through the hard times and celebrated together when experiments actually work. She brings balance to my life and so much more. Julie works harder than anyone I know. Sometimes trying to keep up with her wears me out, but I thrive off of her energy. A life with Julie is worth a thousand lives with anyone else. Julie is not the only friend I have made in graduate school. Nelson Lau and I have been great friends since our first year at MIT. He has been a great sounding board for life's trials and tribulations over the last several years. He and his wife, Dianne Schwarz, are among the nicest, most generous people I've met. Another extremely dependable friend over the years has been Tate Kauffman, who I met while working in the lab of Phil Meneely at Haverford College. He and I thought we might be distant cousins once, due to the potential for shared ancestry in central Pennsylvania. Regardless of the biology, Tate, along with his wife Lara, will always be family to me (even if they are both M.D.s). I would like to thank some of the other friends I have had the pleasure to work with the past several years. Alexander Gimelbrant has been a great lab neighbor for the last 5 years. I will miss his humor and his advice. Nandita Singh did a wonderful job of teaching me the FISH technique. I appreciate all of the work that she and Sasha Ebrahimi did with respect to the first characterization of coordination that laid the groundwork for the rest of my thesis. Michael Tackett and I have suffered together at times, but I have been glad to have someone to complain to. John Hutchinson and Guilherme Neves have been wonderful colleagues and friends, brightening everyone's path that crosses theirs. These are not the only friends I have made in lab. I would like to express my deepest thanks to Andy Chess for being not only and advisor but a friend. I expect that both of us will be in this business for quite some time and it's nice to know that I will have a very creative friend and advisor to call upon when times get tough. My thesis committee members, David Page and Paul Garrity have provided me with great support and guidance over the years. I will miss our discussions and the reassurance of having them in my corner through all these years. I also would like to thank the Howard Hughes Medical Institute for supporting me as a predoctoral fellow. It has meant a lot to me to be a part of such a great program. I would also like to thank my college advisor and genetics professor, Philip Meneely. Phil showed me that biology is a dynamic science. Without him, I know that I would have been an economics major and my life would have taken a totally different path. So I guess what I'm trying to say is that this is all Phil's fault. 4 TABLE OF CONTENTS Chapter One: Introduction: Monoallelic Expression and Asynchronous Replication 7 The comparative value of haploidy versus diploidy 8 Dosage compensation mechanisms in worms and flies 10 Dosage compensation in mammals: X-chromosome inactivation 12 A number of autosomal genes are monoallelically expressed in mammals 19 Asynchronous replication coincides with monoallelic expression 28 Prevalence of asynchronous replication and monoallelic expression 35 Coordination of asynchronous replication between disparate loci 36 Summary of Thesis 39 References 43 Chapter Two: Coordinated replication timing of monoallelically expressed genes along human autosomes. 59 Abstract 60 Introduction 61 Results 63 Asynchronous replication in humans 63 Coordination of asynchronous replication in human cells 68 Asynchronous replication in trisomies 75 Discussion 81 Materials and Methods 85 Acknowledgements 87 References 88 Chapter Three: A search for Xist-like nuclear transcripts in the human genome identifies two conserved noncoding RNAs on Chromosome 11 90 Abstract 91 Introduction 92 Results 95 An array-based approach to identify ubiquitously expressed nuclear RNAs 95 Two noncoding RNAs enriched in the nuclei of human cells 97 RNA FISH of Xist, NEAT], and NEAT2 100 Examining transcription around NEATI and NEAT2 104 Functional analysis of NEAT] and NEAT2 using RNA interference 105 Comparative genomic analysis of hNEATI and hNEAT2 106 Discussion 114 Materials and Methods 117 References
Recommended publications
  • Genetic Variation Across the Human Olfactory Receptor Repertoire Alters Odor Perception

    Genetic Variation Across the Human Olfactory Receptor Repertoire Alters Odor Perception

    bioRxiv preprint doi: https://doi.org/10.1101/212431; this version posted November 1, 2017. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY 4.0 International license. Genetic variation across the human olfactory receptor repertoire alters odor perception Casey Trimmer1,*, Andreas Keller2, Nicolle R. Murphy1, Lindsey L. Snyder1, Jason R. Willer3, Maira Nagai4,5, Nicholas Katsanis3, Leslie B. Vosshall2,6,7, Hiroaki Matsunami4,8, and Joel D. Mainland1,9 1Monell Chemical Senses Center, Philadelphia, Pennsylvania, USA 2Laboratory of Neurogenetics and Behavior, The Rockefeller University, New York, New York, USA 3Center for Human Disease Modeling, Duke University Medical Center, Durham, North Carolina, USA 4Department of Molecular Genetics and Microbiology, Duke University Medical Center, Durham, North Carolina, USA 5Department of Biochemistry, University of Sao Paulo, Sao Paulo, Brazil 6Howard Hughes Medical Institute, New York, New York, USA 7Kavli Neural Systems Institute, New York, New York, USA 8Department of Neurobiology and Duke Institute for Brain Sciences, Duke University Medical Center, Durham, North Carolina, USA 9Department of Neuroscience, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania, USA *[email protected] ABSTRACT The human olfactory receptor repertoire is characterized by an abundance of genetic variation that affects receptor response, but the perceptual effects of this variation are unclear. To address this issue, we sequenced the OR repertoire in 332 individuals and examined the relationship between genetic variation and 276 olfactory phenotypes, including the perceived intensity and pleasantness of 68 odorants at two concentrations, detection thresholds of three odorants, and general olfactory acuity.
  • 1 Long-Read Genome Sequencing for the Diagnosis Of

    1 Long-Read Genome Sequencing for the Diagnosis Of

    bioRxiv preprint doi: https://doi.org/10.1101/2020.07.02.185447; this version posted September 14, 2020. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY-ND 4.0 International license. Long-read genome sequencing for the diagnosis of neurodevelopmental disorders Susan M. Hiatt1, James M.J. Lawlor1, Lori H. Handley1, Ryne C. Ramaker1, Brianne B. Rogers1,2, E. Christopher Partridge1, Lori Beth Boston1, Melissa Williams1, Christopher B. Plott1, Jerry Jenkins1, David E. Gray1, James M. Holt1, Kevin M. Bowling1, E. Martina Bebin3, Jane Grimwood1, Jeremy Schmutz1, Gregory M. Cooper1* 1HudsonAlpha Institute for Biotechnology, Huntsville, AL, USA, 35806 2Department of Genetics, University of Alabama at Birmingham, Birmingham, AL, USA, 35924 3Department of Neurology, University of Alabama at Birmingham, Birmingham, AL, USA, 35924 *[email protected], 256-327-9490 Conflicts of Interest The authors all declare no conflicts of interest. 1 bioRxiv preprint doi: https://doi.org/10.1101/2020.07.02.185447; this version posted September 14, 2020. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY-ND 4.0 International license. Abstract Purpose Exome and genome sequencing have proven to be effective tools for the diagnosis of neurodevelopmental disorders (NDDs), but large fractions of NDDs cannot be attributed to currently detectable genetic variation. This is likely, at least in part, a result of the fact that many genetic variants are difficult or impossible to detect through typical short-read sequencing approaches.
  • The N-Cadherin Interactome in Primary Cardiomyocytes As Defined Using Quantitative Proximity Proteomics Yang Li1,*, Chelsea D

    The N-Cadherin Interactome in Primary Cardiomyocytes As Defined Using Quantitative Proximity Proteomics Yang Li1,*, Chelsea D

    © 2019. Published by The Company of Biologists Ltd | Journal of Cell Science (2019) 132, jcs221606. doi:10.1242/jcs.221606 TOOLS AND RESOURCES The N-cadherin interactome in primary cardiomyocytes as defined using quantitative proximity proteomics Yang Li1,*, Chelsea D. Merkel1,*, Xuemei Zeng2, Jonathon A. Heier1, Pamela S. Cantrell2, Mai Sun2, Donna B. Stolz1, Simon C. Watkins1, Nathan A. Yates1,2,3 and Adam V. Kwiatkowski1,‡ ABSTRACT requires multiple adhesion, cytoskeletal and signaling proteins, The junctional complexes that couple cardiomyocytes must transmit and mutations in these proteins can cause cardiomyopathies (Ehler, the mechanical forces of contraction while maintaining adhesive 2018). However, the molecular composition of ICD junctional homeostasis. The adherens junction (AJ) connects the actomyosin complexes remains poorly defined. – networks of neighboring cardiomyocytes and is required for proper The core of the AJ is the cadherin catenin complex (Halbleib and heart function. Yet little is known about the molecular composition of the Nelson, 2006; Ratheesh and Yap, 2012). Classical cadherins are cardiomyocyte AJ or how it is organized to function under mechanical single-pass transmembrane proteins with an extracellular domain that load. Here, we define the architecture, dynamics and proteome of mediates calcium-dependent homotypic interactions. The adhesive the cardiomyocyte AJ. Mouse neonatal cardiomyocytes assemble properties of classical cadherins are driven by the recruitment of stable AJs along intercellular contacts with organizational and cytosolic catenin proteins to the cadherin tail, with p120-catenin β structural hallmarks similar to mature contacts. We combine (CTNND1) binding to the juxta-membrane domain and -catenin β quantitative mass spectrometry with proximity labeling to identify the (CTNNB1) binding to the distal part of the tail.
  • Mouse Ppef1 Knockout Project (CRISPR/Cas9)

    Mouse Ppef1 Knockout Project (CRISPR/Cas9)

    https://www.alphaknockout.com Mouse Ppef1 Knockout Project (CRISPR/Cas9) Objective: To create a Ppef1 knockout Mouse model (C57BL/6J) by CRISPR/Cas-mediated genome engineering. Strategy summary: The Ppef1 gene (NCBI Reference Sequence: NM_011147 ; Ensembl: ENSMUSG00000062168 ) is located on Mouse chromosome X. 16 exons are identified, with the ATG start codon in exon 1 and the TAA stop codon in exon 16 (Transcript: ENSMUST00000071204). Exon 2~4 will be selected as target site. Cas9 and gRNA will be co-injected into fertilized eggs for KO Mouse production. The pups will be genotyped by PCR followed by sequencing analysis. Note: Homozygous null female and hemizygous null male mice are viable, fertile and display no overt abnormalities. Exon 2 starts from about 2.41% of the coding region. Exon 2~4 covers 18.41% of the coding region. The size of effective KO region: ~10105 bp. The KO region does not have any other known gene. Page 1 of 8 https://www.alphaknockout.com Overview of the Targeting Strategy Wildtype allele 5' gRNA region gRNA region 3' 1 2 3 4 16 Legends Exon of mouse Ppef1 Knockout region Page 2 of 8 https://www.alphaknockout.com Overview of the Dot Plot (up) Window size: 15 bp Forward Reverse Complement Sequence 12 Note: The 2000 bp section upstream of Exon 2 is aligned with itself to determine if there are tandem repeats. No significant tandem repeat is found in the dot plot matrix. So this region is suitable for PCR screening or sequencing analysis. Overview of the Dot Plot (down) Window size: 15 bp Forward Reverse Complement Sequence 12 Note: The 2000 bp section downstream of Exon 4 is aligned with itself to determine if there are tandem repeats.
  • Searching the Genomes of Inbred Mouse Strains for Incompatibilities That Reproductively Isolate Their Wild Relatives

    Searching the Genomes of Inbred Mouse Strains for Incompatibilities That Reproductively Isolate Their Wild Relatives

    Journal of Heredity 2007:98(2):115–122 ª The American Genetic Association. 2007. All rights reserved. doi:10.1093/jhered/esl064 For permissions, please email: [email protected]. Advance Access publication January 5, 2007 Searching the Genomes of Inbred Mouse Strains for Incompatibilities That Reproductively Isolate Their Wild Relatives BRET A. PAYSEUR AND MICHAEL PLACE From the Laboratory of Genetics, University of Wisconsin, Madison, WI 53706. Address correspondence to the author at the address above, or e-mail: [email protected]. Abstract Identification of the genes that underlie reproductive isolation provides important insights into the process of speciation. According to the Dobzhansky–Muller model, these genes suffer disrupted interactions in hybrids due to independent di- vergence in separate populations. In hybrid populations, natural selection acts to remove the deleterious heterospecific com- binations that cause these functional disruptions. When selection is strong, this process can maintain multilocus associations, primarily between conspecific alleles, providing a signature that can be used to locate incompatibilities. We applied this logic to populations of house mice that were formed by hybridization involving two species that show partial reproductive isolation, Mus domesticus and Mus musculus. Using molecular markers likely to be informative about species ancestry, we scanned the genomes of 1) classical inbred strains and 2) recombinant inbred lines for pairs of loci that showed extreme linkage disequi- libria. By using the same set of markers, we identified a list of locus pairs that displayed similar patterns in both scans. These genomic regions may contain genes that contribute to reproductive isolation between M. domesticus and M.
  • A Computational Approach for Defining a Signature of Β-Cell Golgi Stress in Diabetes Mellitus

    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.
  • A Large Genome-Wide Association Study of Age-Related Macular Degeneration Highlights Contributions of Rare and Common Variants

    A Large Genome-Wide Association Study of Age-Related Macular Degeneration Highlights Contributions of Rare and Common Variants

    A large genome-wide association study of age-related macular degeneration highlights contributions of rare and common variants The Harvard community has made this article openly available. Please share how this access benefits you. Your story matters Citation Fritsche, L. G., W. Igl, J. N. Cooke Bailey, F. Grassmann, S. Sengupta, J. L. Bragg-Gresham, K. P. Burdon, et al. 2016. “A large genome-wide association study of age-related macular degeneration highlights contributions of rare and common variants.” Nature genetics 48 (2): 134-143. doi:10.1038/ng.3448. http:// dx.doi.org/10.1038/ng.3448. Published Version doi:10.1038/ng.3448 Citable link http://nrs.harvard.edu/urn-3:HUL.InstRepos:27662298 Terms of Use This article was downloaded from Harvard University’s DASH repository, and is made available under the terms and conditions applicable to Other Posted Material, as set forth at http:// nrs.harvard.edu/urn-3:HUL.InstRepos:dash.current.terms-of- use#LAA HHS Public Access Author manuscript Author ManuscriptAuthor Manuscript Author Nat Genet Manuscript Author . Author manuscript; Manuscript Author available in PMC 2016 June 21. Published in final edited form as: Nat Genet. 2016 February ; 48(2): 134–143. doi:10.1038/ng.3448. A large genome-wide association study of age-related macular degeneration highlights contributions of rare and common variants A full list of authors and affiliations appears at the end of the article. Abstract Advanced age-related macular degeneration (AMD) is the leading cause of blindness in the elderly with limited therapeutic options. Here, we report on a study of >12 million variants including 163,714 directly genotyped, most rare, protein-altering variant.
  • 'Histology and Immunophenotype of Invasive Lobular Breast Cancer

    'Histology and Immunophenotype of Invasive Lobular Breast Cancer

    Varga, Z; Mallon, E (2009). Histology and Immunophenotype of Invasive Lobular Breast Cancer. Daily Practice and Pitfalls. Breast Disease, 30:15-19. Postprint available at: http://www.zora.uzh.ch University of Zurich Posted at the Zurich Open Repository and Archive, University of Zurich. Zurich Open Repository and Archive http://www.zora.uzh.ch Originally published at: Breast Disease 2009, 30:15-19. Winterthurerstr. 190 CH-8057 Zurich http://www.zora.uzh.ch Year: 2009 Histology and Immunophenotype of Invasive Lobular Breast Cancer. Daily Practice and Pitfalls Varga, Z; Mallon, E Varga, Z; Mallon, E (2009). Histology and Immunophenotype of Invasive Lobular Breast Cancer. Daily Practice and Pitfalls. Breast Disease, 30:15-19. Postprint available at: http://www.zora.uzh.ch Posted at the Zurich Open Repository and Archive, University of Zurich. http://www.zora.uzh.ch Originally published at: Breast Disease 2009, 30:15-19. Histology and Immunophenotype of Invasive Lobular Breast Cancer. Daily Practice and Pitfalls Abstract Invasive lobular carcinomas (ILC) represent the most common subtype of invasive breast cancer and account for about 5-15% of all breast cancer cases. Invasive lobular carcinoma is often accompanied by in situ lesions, by lobular neoplasia (LN). Invasive lobular carcinomas display diverse histologic patterns varying from classical through solid to pleomorphic subtypes. When analyzing histological subtypes, the classical variant is reported to have a more favorable outcome. The majority of invasive lobular carcinomas are hormone receptor positive, overexpression and/or amplification of the Her2 gene is lower than in carcinomas of invasive ductal type. Loss of heterozygosity of the 16q chromosomal regions and the consequent lack of E-Cadherin expression are common findings in invasive lobular carcinomas.
  • Blood Flow Guides Sequential Support of Neutrophil Arrest and Diapedesis

    Blood Flow Guides Sequential Support of Neutrophil Arrest and Diapedesis

    RESEARCH ARTICLE Blood flow guides sequential support of neutrophil arrest and diapedesis by PILR-b 1 and PILR-a Yu-Tung Li, Debashree Goswami†, Melissa Follmer, Annette Artz, Mariana Pacheco-Blanco, Dietmar Vestweber* Vascular Cell Biology, Max Planck Institute of Molecular Biomedicine, Mu¨ nster, Germany Abstract Arrest of rapidly flowing neutrophils in venules relies on capturing through selectins and chemokine-induced integrin activation. Despite a long-established concept, we show here that gene inactivation of activating paired immunoglobulin-like receptor (PILR)-b1 nearly halved the efficiency of neutrophil arrest in venules of the mouse cremaster muscle. We found that this receptor binds to CD99, an interaction which relies on flow-induced shear forces and boosts chemokine-induced b2-integrin-activation, leading to neutrophil attachment to endothelium. Upon arrest, binding of PILR-b1 to CD99 ceases, shifting the signaling balance towards inhibitory PILR-a. This enables integrin deactivation and supports cell migration. Thus, flow-driven shear forces guide sequential signaling of first activating PILR-b1 followed by inhibitory PILR-a to prompt neutrophil arrest and then transmigration. This doubles the efficiency of selectin-chemokine driven neutrophil arrest by PILR-b1 and then supports transition to migration by PILR-a. DOI: https://doi.org/10.7554/eLife.47642.001 *For correspondence: [email protected] Present address: †Center for Global Infectious Disease Introduction Research, Seattle Childrens Host defense against pathogens depends on the recruitment of leukocytes to sites of infections Research Institute, Seattle, (Ley et al., 2007). Selectins capture leukocytes to the endothelial cell surface by binding to glyco- United States conjugates (McEver, 2015).
  • Hormonal Regulation of TSEI-Repressed Genes:Evidence

    Hormonal Regulation of TSEI-Repressed Genes:Evidence

    MOLECULAR AND CELLULAR BIOLOGY, JUlY 1989, p. 2837-2846 Vol. 9, No. 7 0270-7306/89/072837-10$02.00/0 Copyright C) 1989, American Society for Microbiology Hormonal Regulation of TSEI-Repressed Genes: Evidence for Multiple Genetic Controls in Extinction MATHEW J. THAYER AND R. E. K. FOURNIER* Department of Molecul(ar Medicine, Fred Hiutchinson Cancer Research Center, 1124 Columbia Street, Seattle, Washington 98104 Received 9 January 1989/Accepted 26 March 1989 Somatic cell hybrids formed by fusing hepatoma cells with fibroblasts generally fail to express liver functions, a phenomenon termed extinction. Previous studies demonstrated that extinction of the genes encoding tyrosine aminotransferase, phosphoenolpyruvate carboxykinase, and argininosuccinate synthetase is mediated by a specific genetic locus (TSEI) that maps to mouse chromosome 11 and human chromosome 17. In this report, we show that full repression of these genes requires a genetic factor in addition to TSE1. This conclusion is based on the observation that residual gene activity was apparent in monochromosomal hybrids retaining human TSEI but not in complex hybrids retaining many fibroblast chromosomes. Furthermore, TSE1- repressed genes were hormone inducible, whereas fully extinguished genes were not. Analysis of hybrid segregants indicated that genetic loci required for the complete repression phenotype were distinct from TSE1. Tissue-specific gene expression in mammalian cells is ing that single fibroblast chromosome are extinguished for primarily regulated at the level of transcription (8). A par- both serum albumin and alcohol dehydrogenase gene activ- ticular gene may account for a large fraction of total tran- ity (A. C. Chin and R. E. K. Fournier, submitted for publi- scription in one cell type yet be virtually silent in other cell cation).
  • 134 Mb (Almost the Same As the Size of Chromosome 10). It Is ~4–4.5% of the Total Human Genome

    134 Mb (Almost the Same As the Size of Chromosome 10). It Is ~4–4.5% of the Total Human Genome

    Chromosome 11 ©Chromosome Disorder Outreach Inc. (CDO) Technical genetic content provided by Dr. Iosif Lurie, M.D. Ph.D Medical Geneticist and CDO Medical Consultant/Advisor. Ideogram courtesy of the University of Washington Department of Pathology: ©1994 David Adler.hum_11.gif Introduction The genetic size of chromosome 11 is ~134 Mb (almost the same as the size of chromosome 10). It is ~4–4.5% of the total human genome. The length of its short arm is ~50 Mb; the length of its long arm in ~84 Mb. Chromosome 11 is a very gene–rich area. It contains ~1,500 genes. Mutations of ~200 of these genes are known to cause birth defects or some functional abnormalities. The short arm of chromosome 11 contains a region which is known to be imprinted. As a result duplications of this region will have different manifestations depending on the sex of the parent responsible for this defect. Phenotypes of persons with duplications of the maternal origin will be different from the phenotypes of the persons with a paternal duplication of the same area. There are ~1,400 patients with different structural abnormalities of chromosome 11 as the only abnormality or in association with abnormalities for other chromosomes. At least 800 of these patients had different deletions of chromosome 11. Deletions of the short arm have been reported in ~250 patients (including those with an additional imbalance); deletions of the long arm have been described in ~550 patients. There are two syndromes caused by deletions of the short arm (both of these syndromes have been known for several years) and one well–known syndrome caused by distal deletions of the long arm (Jacobsen syndrome).
  • The Human Gene Encoding Phosphatidylinositol-3 Kinase Associated P85a Is at Chromosome Region 5Ql2-13'

    The Human Gene Encoding Phosphatidylinositol-3 Kinase Associated P85a Is at Chromosome Region 5Ql2-13'

    [CANCER RESEARCH 5l. .1818-.1820, July 15, 1991| Advances in Brief The Human Gene Encoding Phosphatidylinositol-3 Kinase Associated p85a Is at Chromosome Region 5ql2-13' L. A. Cannizzaro, E. Y. Skolnik, B. Margolis, C. M. Croce, J. Schlesinger, and K. Huebner2 Fels Institute for Cancer Research and Molecular Biology, Temple University School of Medicine, Philadelphia, Pennsylvania 19140 [L. A. C., C. M. C., K. H.J, and Department of Pharmacology, New York University Medical Center, New York, New York 10016 [E. Y. S., B. M., J. S.J Abstract scribed previously (10, 11). Hybrids 9142 (full name GM9142), 114 (GM100114), 115 (GM100115), 7297 (GM7297), 7300 (GM7300), I In' human chromosomal location of the gene encoding the phospha- 449 (GM10449), 10095 (GM10095), and 7301 (GM7301) were ob tidylinositol-3 kinase associated protein, p85a, has been determined by tained from the National Institute of General Medical Sciences Human analysis of its segregation in rodent-human hybrids and by chromosome Genetic Mutant Cell Repository (Corieli Institute for Medical Re in situ hybridization using a complementary DNA clone, GRB-1. search, Camden, NJ). Human chromosomes or chromosome regions The gene for p85<*is at chromosome region 5ql3, perhaps near the retained by individual hybrids in the panel are illustrated in Fig. 1. gene encoding another receptor associated signal transducing protein, the Hybrids retaining partial chromosome 5 have also been described GTPase activating protein. previously (12). Filter Hybridization. DNA from mouse, human, and hybrid cell lines Introduction was obtained by a standard phenol-chloroform extraction procedure (10). Approximately 10 Mgof DNA were digested to completion with Skolnik et al.