DOCSLIB.ORG

Gene Expression Β (Ig B29 Silencer

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
Gene Expression Β (Ig B29 Silencer An Upstream Oct-1- and Oct-2-Binding Silencer Governs B29 (Igβ) Gene Expression Cindy Sue Malone, Lisa Patrone, Kent L. Buchanan, Carol F. Webb and Randolph Wall This information is current as of September 24, 2021. J Immunol 2000; 164:2550-2556; ; doi: 10.4049/jimmunol.164.5.2550 http://www.jimmunol.org/content/164/5/2550 Downloaded from References This article cites 55 articles, 26 of which you can access for free at: http://www.jimmunol.org/content/164/5/2550.full#ref-list-1 Why The JI? Submit online. http://www.jimmunol.org/ • Rapid Reviews! 30 days* from submission to initial decision • No Triage! Every submission reviewed by practicing scientists • Fast Publication! 4 weeks from acceptance to publication *average by guest on September 24, 2021 Subscription Information about subscribing to The Journal of Immunology is online at: http://jimmunol.org/subscription Permissions Submit copyright permission requests at: http://www.aai.org/About/Publications/JI/copyright.html Email Alerts Receive free email-alerts when new articles cite this article. Sign up at: http://jimmunol.org/alerts The Journal of Immunology is published twice each month by The American Association of Immunologists, Inc., 1451 Rockville Pike, Suite 650, Rockville, MD 20852 Copyright © 2000 by The American Association of Immunologists All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. An Upstream Oct-1- and Oct-2-Binding Silencer Governs B29 (Ig␤) Gene Expression1 Cindy Sue Malone,* Lisa Patrone,* Kent L. Buchanan,2† Carol F. Webb,† and Randolph Wall3* The B cell-specific B29 (Ig␤) gene is activated in the earliest B cell precursors and is expressed throughout B cell development. Tissue-specific expression of the murine B29 gene is controlled by a B cell-specific promoter whose activity is governed by a cassette of upstream transcriptional silencers. This study describes a potent new silencer that is located 5؅ of the previously identified B29 silencer elements, FROG and TOAD. Like these known elements, the new B29 silencer is not restricted to the B29 promoter. Nuclear proteins from all cell lines tested interacted with this A؉T-rich sequence, which closely resembled a noncanonical octamer binding motif and also conformed to the consensus sequence for nuclear matrix attachment regions. Interaction of Oct-1 and Oct-2 with the B29 A؉T-rich sequence was confirmed using octamer-specific Abs. Oct-1/Oct-2 binding was required for the inhibitory activity of this sequence because mutations that blocked Oct-1/Oct-2 binding also eliminated inhibition of the B29 promoter. This Downloaded from B29 A؉T-rich sequence specifically interacted with isolated nuclear matrix proteins in vitro, suggesting that it may also function as a matrix attachment region element. Maintenance of the level of B29 gene expression through the interaction of the minimal promoter and the upstream silencer elements FROG, TOAD, and the A؉T-rich Oct-1/Oct-2 binding motif may be essential for normal B cell development and/or function. The Journal of Immunology, 2000, 164: 2550–2556. ␤ he product of the B29 (Ig ) gene is an essential compo- Oct-1 and Oct-2 transcription factors (6). This octamer motif is a http://www.jimmunol.org/ nent of the B cell receptor (BCR)4 that plays an indis- major determinant of B29 promoter activity in that mutations that T pensable role in B cell development. The B29 gene prod- eliminated Oct-1 and Oct-2 binding also abolished B29 promoter uct is disulfide-linked to the mb-1 (Ig␣) gene product, and this function (5). heterodimer is associated with Ig to form functional BCR com- Expression of the B29 minimal promoter is also regulated by plexes on B cells. B29-mb-1 heterodimers control VDJH recombi- upstream transcription control elements with inhibitory activities. nation, allelic exclusion, surface translocation of Ig, and signal We previously identified two silencer elements, FROG and transduction events that occur through the BCR (reviewed in Refs. TOAD, upstream of the B29 minimal promoter that coordinately 1–3). govern its level of expression (7). To date, the FROG- and TOAD- Due to the critical role the B29 gene plays in B cell maturation interacting proteins have not been identified. These B29 silencer by guest on September 24, 2021 and function, we have characterized the features regulating its tran- elements are equally active in both orientations, are position-inde- scription and B cell specificity. Previously, we demonstrated that pendent, can affect heterologous promoters, and are not tissue re- the B cell specificity of B29 is determined by a minimal promoter stricted (7). These features of the B29 silencers resemble other that contains multiple transcription factor motifs that collectively functionally defined cis-acting negative regulatory DNA se- determine its tissue specificity and transcriptional activity. These quences that down-regulate gene transcription and belong to the motifs include early B cell factor, Ikaros, ETS, SP1, and octamer class of silencer elements that restrict levels of gene expression (4, 5). The B29 octamer motif was shown to interact with both rather than impart tissue specificity. Other examples of silencers reported to govern gene expression like the B29 silencer are *Department of Microbiology and Immunology, and Molecular Biology Institute, present in the bcl-2 (8), ETS-1 (9), and ␭5 (10) genes. It has been University of California, School of Medicine, Los Angeles, CA 90095; and †Immu- nobiology and Cancer Program, Oklahoma Medical Research Foundation, Oklahoma postulated that this class of inhibitory transcription control ele- City, OK 73104 ments functions in maintaining the level of specific gene expres- Received for publication October 18,1999. Accepted for publication December sion, thereby preventing deleterious consequences of overexpres- 16, 1999. sion (7). For example, moderate overexpression of bcl-2 is linked The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance to the prolonged survival of neoplastic B cells in follicular lym- with 18 U.S.C. Section 1734 solely to indicate this fact. phoma and chronic lymphocytic leukemia (11, 12). bcl-2 is gov- 1 This work was supported by National Institutes of Health Grants CA12800 and erned by silencer elements similar in nature to the silencers of the GM40185 and University of California Amgen STAR Biotechnology Project S96-02 B29 gene in that they affect bcl-2 expression levels but do not (to R.W.); and by National Institutes of Health Grants GM46462 and AI44215 (to ⑀ C.F.W.). C.S.M. was supported by Public Health Service National Service Award impart tissue specificity (8). Elevated CD3 expression in T cells AI07126, the Dr. Ursula Mandel Scholarship, and the University of California Dis- blocked early T cell development (13) and in prothymocytes func- sertation Year Fellowship. L.P. was supported by Public Health Service National ⑀ Research Service Award 2T32 CA 09120. tioned as an oncogene (14). These consequences of CD3 gene overexpression are particularly relevant in that CD3⑀ fulfills the 2 Current address: Department of Microbiology and Immunology, Tulane University Medical Center, New Orleans, LA 70112 same role in the TCR as B29 does in the BCR. 3 Address correspondence and reprint requests to Dr. Randolph Wall, University of Further functional analysis of the region upstream of the B29 California, 611 Charles E. Young Drive East, 529 Molecular Biology Institute, Los minimal promoter has identified a new region of potent silencer Angeles, CA 90095. E-mail address: [email protected] activity 5Ј of the previously identified FROG and TOAD silencer 4 Abbreviations used in this paper: BCR, B cell receptor; MAR, matrix attachment region; CAT, chloramphenicol acetyltransferase; RSV, Rous sarcoma virus; Bright, B elements. Like these previously characterized B29 silencer ele- cell regulator of IgH transcription. ments, this new 5Ј B29 silencer is not B29 promoter-restricted. Copyright © 2000 by The American Association of Immunologists 0022-1767/00/$02.00 The Journal of Immunology 2551 DNase I protection assays over this region delineated a well-de- fined protected area with an extended central AϩT-rich sequence. This central AϩT-rich sequence is homologous to the degenerate AϩT-rich motifs recognized by octamer transcription factor fam- ily members (15). Both Oct-1 and Oct-2 factors bound the B29 AϩT-rich sequence in EMSA. Site-directed mutations incorpo- rated into this AϩT-rich predicted octamer motif eliminated Oct-1 and Oct-2 binding, which in turn abolished the silencer activity of this region. The B29 AϩT-rich sequence also conforms to all the consensus sequence criteria for nuclear matrix attachment regions (MARs). MARs mediate chromatin association with the nuclear matrix (16, 17), are usually located within or near transcriptional regulatory elements (18–22), and are postulated to function in regulating gene expression by acting as boundary elements for transcription (20), by creating altered nucleosome environments (23, 24), and by af- FIGURE 1. B29 AϩT-rich motif contributes to the negative regulation fecting enhancer and silencer functions by impacting chromatin of the B29 minimal (Ϫ164) promoter. Transient transfection to detect tran- structure (25–27). The B29 AϩT-rich sequence selectively inter- scriptional expression of B29 promoter deletion constructs were conducted acted with nuclear matrix proteins, suggesting that this segment in the M12 B cell line. The activity of each construct is expressed as a Downloaded from may also function as a MAR in B29 gene control. percentage of the CAT activity obtained with the B29 (Ϫ164) minimal promoter construct (100%). Deletion construct Ϫ411 was created to sep- Materials and Methods arate the activities of the AϩT-rich motif from the FROG motif silencer ϩ Plasmid construction and mutagenesis element to determine transcriptional activity of the A T-rich motif region.
Load more

Recommended publications
  • Involvement of REST Corepressor 3 in Prognosis of Human Hepatitis B
    Acta Pharmacologica Sinica (2011) 32: 1019–1024 npg © 2011 CPS and SIMM All rights reserved 1671-4083/11 $32.00 www.nature.com/aps Original Article Involvement of REST corepressor 3 in prognosis of human hepatitis B Ji-hua XUE, Min ZHENG, Xiao-wei XU, Shan-shan WU, Zhi CHEN, Feng CHEN* State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, the First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou 310003, China Aim: To examine the potential correlation between serum REST corepressor 3 (RCOR3) level and the outcome of patients with hepa-­­ titis B. Methods: Concanavalin A (ConA)-induced mouse hepatitis model was used. The mRNA level of RCOR3 in mouse liver was measured using GeneChip array and real-time PCR. One hundred seventy-seven patients with hepatitis B and 34 healthy individuals were catego- rized into six groups including mild chronic hepatitis, moderate chronic hepatitis B, severe hepatitis B (SHB), cirrhosis, hepatocellular carcinoma (HCC) and healthy control. Serum levels of human RCOR3 were measured using ELISA. Results: In the mouse hepatitis model, the mRNA level of RCOR3 in liver was reduced early after exposure to ConA, then increased after 6 h of exposure. There was no significant difference in the serum RCOR3 level between the mild chronic hepatitis B and the con- trol groups. The serum RCOR3 level was significantly increased in the moderate chronic hepatitis B group, but significantly reduced in SHB, cirrhosis and HCC groups, as compared with the control group. Moreover, the serum RCOR3 levels in SHB, cirrhosis and liver cancer patients were significantly lower than those in the patients with moderate chronic hepatitis B and with mild chronic hepatitis B.
    [Show full text]
  • Silencer Elements Controlling the B29 (Ig␤) Promoter Are Neither Promoter- Nor Cell-Type-Specific
    Proc. Natl. Acad. Sci. USA Vol. 94, pp. 12314–12319, November 1997 Biochemistry Silencer elements controlling the B29 (Igb) promoter are neither promoter- nor cell-type-specific CINDY SUE MALONE*, SIDNE A. OMORI*†, AND RANDOLPH WALL*‡ *Molecular Biology Institute and Department of Microbiology and Immunology, University of California, Los Angeles, School of Medicine, Los Angeles, CA 90095 Communicated by David S. Eisenberg, University of California, Los Angeles, CA, July 11, 1997 (received for review May 9, 1997) ABSTRACT The murine B29 (Igb) promoter is B cell combinatorial activities of this cassette of different transcrip- specific and contains essential SP1, ETS, OCT, and Ikaros tion factors (11, 20). motifs. Flanking 5* DNA sequences inhibit B29 promoter The current study focuses on the B29 regulatory region 59 of activity, suggesting this region contains silencer elements. the murine minimal B29 promoter. Deletion analyses of the Two adjacent 5* DNA segments repress transcription by the B29 gene 59 flanking region revealed two adjacent regions with murine B29 promoter in a position- and orientation- significantly lower transcriptional activity than the minimal independent manner, analogous to known silencers. Both promoter, suggesting the presence of silencer elements. Si- these 5* segments also inhibit transcription by several heter- lencers are functionally defined cis-acting regulatory DNA ologous promoters in B cells, including mb-1, c-fos, and human elements that down-regulate gene transcription. They gener- B29. These 5* segments also inhibit transcription by the c-fos ally exhibit activity in either orientation, may be either posi- promoter in T cells suggesting they are not B cell-specific tion-dependent or -independent, and may or may not affect elements.
    [Show full text]
  • Robijn Bruinsma
    Opportunities for Theory in Biological Physics. 1) Chromosome Control. 2) The Polyglutamine Problem. 3) Transcription Initiation Complex. 4) Ribosomal Proofreading. 5) Focal Adhesion Sites. *DNA/DNA interaction: Aqueous electrostatics beyond mean-field theory. (Oosawa) *DNA/nucleosome interaction: electrostatic attraction versus bending stiffness. (Manning) *Micromechanics (M.Wang) Nucleus: 23 chromosomes (1m DNA in micron-sized nucleus) Gene regulation by compaction. “Chromosome painting”: 3D-FISH Statics: 3-D Reconstruction of Nucleus. DNA-DNA mean spacing: 30-40 Angstrom. Close-packing is close (Cremer) Expanded Chromosome Condensed Loop (active genes) inactive genes Decondensed, active genes Inter-chromatin Compartment Active gene: on surface. Late replicating gene Nucleus is fully accessible to protein transport. 3-D Fish: Chromosome Dynamics (20 minute intervals) Chromosomal “Diffusion” Chromosomal Volume and Surface Area vs time. Statics: How is the “open” architecture of the nucleus maintained and controlled under the osmotic pressure of de-condensed, active DNA sections. Equation of State of DNA bundles is known. Dynamics: Chromosome dynamics driven by DNA condensation/de-conden- sation events triggered by local gene expression:”gene noise”. *Can we deduce temporal and spatial correlation functions for gene noise from the motion of the chromosomes by fluctuation analysis and relate it to gene activity? *Chromosome “micro-rheology”? The Polyglutamine Problem Nine neuro-degenerative diseases are associated with (CAG)N triplet repeats: Huntingdon’s, spinal dystrophy, ataxia …. CAG is the code for the amino-acid glutamine. C. Elegans worm GFP (CAG)N N=19 Homogeneous N=82: Toxic Aggregates Impaired motility Proteosome action N=82 (x 40) inhibited. Aggregates: N > 35-40 In vitro polyglutamine homopolymer aggregation (N=37) Aggregation Kinetics (Wetzel): Chen, Songming et al.
    [Show full text]
  • UNIT 6 from DNA to Protein: Gene Expression PART 2 Hillis Textbook
    UNIT 6 PART 3 *REGULATION USING OPERONS* Hillis Textbook, CH 11 REVIEW: Signals that Start and Stop Transcription and Translation BUT, HOW DO CELLS CONTROL WHICH GENES ARE EXPRESSED AND WHEN? First of all, There is a difference between regulation in a prokaryote and a eukaryote…. OPERONS - PROKARYOTES Prokaryotes conserve energy by making proteins only when needed. The most efficient gene regulation is at the level of transcription. A gene cluster with a single promoter is an operon. An operator is a short stretch of DNA near the promoter that controls transcription of the structural genes. 1. Inducible operon—turned off unless needed In inducible systems—a metabolic substrate (inducer) interacts with a regulatory protein (repressor); the repressor cannot bind and allows transcription. Usually control CATABOLIC REACTIONS 2. Repressible operon—turned on unless not needed In repressible systems—a metabolic product (co-repressor) binds to regulatory protein, which then binds to the operator and blocks transcription. Usually control ANABOLIC REACTIONS. LAC OPERON - INDUCIBLE A compound that induces protein synthesis is an inducer. When the enzymes are induced, metabolism will take place. LAC OPERON – INDUCIBLE E. coli must adapt quickly to supply of food (lactose is a dissacharide example) Uptake and metabolism of lactose involves three important -galactoside enzymes -galactoside is a type of glycosidic bond between monosaccharides… if this is present, LACTOSE is present. If E. coli is grown with glucose but no lactose present, no enzymes for lactose conversion are produced. If lactose is predominant and glucose is low, E. coli synthesizes all three enzymes. If lactose is removed, synthesis stops.
    [Show full text]
  • The Neuron-Restrictive Silencer Element: a Dual Enhancer͞silencer Crucial for Patterned Expression of a Nicotinic Receptor Gene in the Brain
    Proc. Natl. Acad. Sci. USA Vol. 94, pp. 5906–5911, May 1997 Neurobiology The neuron-restrictive silencer element: A dual enhancerysilencer crucial for patterned expression of a nicotinic receptor gene in the brain ALAIN BESSIS*, NICOLAS CHAMPTIAUX,LAURENT CHATELIN, AND JEAN-PIERRE CHANGEUX† Neurobiologie Mole´culaire,UA CNRS D1284, De´partementdes Biotechnologies, Institut Pasteur 25y28 rue du Dr Roux, 75724 Paris Cedex 15 Contributed by Jean-Pierre Changeux, March 24, 1997 ABSTRACT The neuron-restrictive silencer element transcriptional repressing activity on promoters that carry the (NRSE) has been identified in several neuronal genes and NRSE sequence (15, 21, 23). confers neuron specificity by silencing transcription in non- In this work, we have analyzed the function of NRSE in the neuronal cells. NRSE is present in the promoter of the promoter of the mouse gene encoding the nAChR b2-subunit neuronal nicotinic acetylcholine receptor b2-subunit gene as well as the importance of its location within the promoter. that determines its neuron-specific expression in the nervous In transgenic mice, we show that upon mutation of NRSE, the system. Using transgenic mice, we show that NRSE may either pattern of expression of the b2-subunit gene promoter dra- silence or enhance transcription depending on the cellular matically changes but remains restricted to the nervous system. context within the nervous system. In vitro in neuronal cells, We confirm that NRSE in vitro can behave either as an NRSE activates transcription of synthetic promoters when enhancer or as a silencer depending both on the primary located downstream in the 5* untranslated region, or at less structure of the promoter and the type of cell line.
    [Show full text]
  • Transcription in Archaea
    Proc. Natl. Acad. Sci. USA Vol. 96, pp. 8545–8550, July 1999 Evolution Transcription in Archaea NIKOS C. KYRPIDES* AND CHRISTOS A. OUZOUNIS†‡ *Department of Microbiology, University of Illinois at Urbana-Champaign, B103 Chemistry and Life Sciences, MC 110, 407 South Goodwin Avenue, Urbana, IL 61801; and †Computational Genomics Group, Research Programme, The European Bioinformatics Institute, European Molecular Biology Laboratory, Cambridge Outstation, Wellcome Trust Genome Campus, Cambridge CB10 1SD, United Kingdom Edited by Norman R. Pace, University of California, Berkeley, CA, and approved May 11, 1999 (received for review December 21, 1998) ABSTRACT Using the sequences of all the known transcrip- enzyme was found to have a complexity similar to that of the tion-associated proteins from Bacteria and Eucarya (a total of Eucarya (consisting of up to 15 components) (17). Subsequently, 4,147), we have identified their homologous counterparts in the the sequence similarity between the large (universal) subunits of four complete archaeal genomes. Through extensive sequence archaeal and eukaryotic polymerases was demonstrated (18). comparisons, we establish the presence of 280 predicted tran- This discovery was followed by the first unambiguous identifica- scription factors or transcription-associated proteins in the four tion of transcription factor TFIIB in an archaeon, Pyrococcus archaeal genomes, of which 168 have homologs only in Bacteria, woesei (19). Since then, we have witnessed a growing body of 51 have homologs only in Eucarya, and the remaining 61 have evidence confirming the presence of key eukaryotic-type tran- homologs in both phylogenetic domains. Although bacterial and scription initiation factors in Archaea (5, 20). Therefore, the eukaryotic transcription have very few factors in common, each prevailing view has become that Archaea and Eucarya share a exclusively shares a significantly greater number with the Ar- transcription machinery that is very different from that of Bac- chaea, especially the Bacteria.
    [Show full text]
  • Identification of Potential Target Genes for the Neuron-Restrictive Silencer Factor CHRISTOPHER J
    Proc. Natl. Acad. Sci. USA Vol. 93, pp. 9881-9886, September 1996 Neurobiology Identification of potential target genes for the neuron-restrictive silencer factor CHRISTOPHER J. SCHOENHERR*t, ALICE J. PAQUETTE*, AND DAVID J. ANDERSON*0§ *Division of Biology 216-76 and tHoward Hughes Medical Institute, California Institute of Technology, Pasadena, CA 91125 Communicated by Melvin I. Simon, California Institute of Technology, Pasadena, CA, June 6, 1996 (received for review March 13, 1996) ABSTRACT The neuron-restrictive silencer factor to most positive regulators of neuronal genes, NRSF activity, (NRSF) represses transcription of several neuronal genes in protein, and mRNA are not present in the majority ofneuronal nonneuronal cells by binding to a 21-bp element called the cells but are instead found in most nonneuronal cell types (18, neuron-restrictive silencer element (NRSE). We have per- 19, 21, 22). Thus, NRSF appears to prevent expression of formed data base searches with a composite NRSE to identify certain neuronal genes in nonneuronal cells. In addition, additional candidate NRSF target genes. Twenty-two more NRSF mRNA is expressed in undifferentiated neural precur- genes, 17 of which are expressed mainly in neurons, were sors (21, 22), suggesting that it may prevent precocious ex- found to contain NRSE-like sequences. Many ofthese putative pression of the neuronal phenotype during neurogenesis. NRSEs bound NRSF in vitro and repressed transcription in A further understanding of NRSF function would be aided vivo. Most of the neuronal genes identified contribute to the by the identification of additional target genes. In this report, basic structural or functional properties of neurons.
    [Show full text]
  • An Auxiliary Silencer and a Boundary Element Maintain High Levels of Silencing Proteins at HMR in Saccharomyces Cerevisiae
    Copyright Ó 2010 by the Genetics Society of America DOI: 10.1534/genetics.109.113100 An Auxiliary Silencer and a Boundary Element Maintain High Levels of Silencing Proteins at HMR in Saccharomyces cerevisiae Patrick J. Lynch and Laura N. Rusche1 Institute for Genome Sciences and Policy and Department of Biochemistry, Duke University, Durham, North Carolina, 27708 Manuscript received December 14, 2009 Accepted for publication February 19, 2010 ABSTRACT Heterochromatin is notable for its capacity to propagate along a chromosome. The prevailing model for this spreading process postulates that silencing proteins are first recruited to silencer sequences and then spread from these sites independently of the silencers. However, we found that in Saccharomyces cerevisiae silencers also influence the extent of silenced chromatin domains. We compared the abilities of two different silencers, HMR-E and a telomeric repeat, to promote silencing and found that the HMR-E silencer contributed to an increased steady-state association of Sir proteins over a region of several kilo- base pairs compared to the telomeric repeat, even though both silencers recruited similar levels of Sir proteins. We also discovered that, although the HMR-E silencer alone was sufficient to block transcription of the HMR locus, a secondary silencer, HMR-I, boosted the level of Sir proteins at HMR, apparently beyond the level necessary to repress transcription. Finally, we discovered that a tRNAThr gene near HMR-I helped maintain silenced chromatin and transcriptional repression under conditions of reduced deacetylase activity. This study highlights the importance of auxiliary elements, such as HMR-I and the tRNAThr gene, in enhancing the association of Sir silencing proteins with appropriate genomic locations, thereby buffering the capacity of silenced chromatin to assemble under suboptimal conditions.
    [Show full text]
  • Evolution of a Tissue-Specific Silencer Underlies Divergence in the Expression of Pax2 and Pax8 Paralogues
    ARTICLE Received 4 Oct 2011 | Accepted 18 Apr 2012 | Published 22 May 2012 DOI: 10.1038/ncomms1851 Evolution of a tissue-specific silencer underlies divergence in the expression of pax2 and pax8 paralogues Haruki Ochi1,2, Tomoko Tamai1, Hiroki Nagano1, Akane Kawaguchi1, Norihiro Sudou1,2 & Hajime Ogino1,2 Recent studies underscore a role for the differential degeneration of enhancers in the evolutionary diversification of paralogue expression. However, no one has reported evidence for the involvement of innovative cis-regulatory changes. Here we show that silencer innovation diversified expression of the vertebrate paralogues, pax2 and pax8. pax2 shows multi-tissue expression, as does the ancestral amphioxus orthologue, pax2/5/8, whereas pax8 expression localizes to a subset of pax2-expressing tissues. We reveal that both pax2 and pax8 retain ancestral enhancers capable of directing pax2-like, multi-tissue expression. However, a silencer within the pax8 proximal promoter suppresses pleiotropic enhancer activity outside the pax8- expressing tissues. In contrast, the combination of the pax2 proximal promoter with either the pax8 or pax2 enhancer recapitulates pax2-like expression, as in the amphioxus pax2/5/8 promoter. We propose that silencer innovation, rather than enhancer degeneration, was crucial for the divergent expression of paralogues with pleiotropic enhancers inherited from their common progenitor. 1 Graduate School of Biological Sciences, Nara Institute of Science and Technology, 8916-5, Takayama, Ikoma, 630-0192, Japan. 2 JST, CREST, Japan. Correspondence and requests for materials should be addressed to H. Ogino (email: [email protected]). NATURE COMMUNICATIONS | 3:848 | DOI: 10.1038/ncomms1851 | www.nature.com/naturecommunications © 2012 Macmillan Publishers Limited.
    [Show full text]
  • Mir-22 As a Metabolic Silencer and Liver Tumor Suppressor
    UC Davis UC Davis Previously Published Works Title MiR-22 as a metabolic silencer and liver tumor suppressor. Permalink https://escholarship.org/uc/item/6jn2b8z9 Journal Liver research, 4(2) ISSN 2096-2878 Authors Wang, Lijun Wang, Yu-Shiuan Mugiyanto, Eko et al. Publication Date 2020-06-09 DOI 10.1016/j.livres.2020.06.001 Peer reviewed eScholarship.org Powered by the California Digital Library University of California Liver Research xxx (xxxx) xxx Contents lists available at ScienceDirect Liver Research journal homepage: http://www.keaipublishing.com/en/journals/liver-research Review Article MiR-22 as a metabolic silencer and liver tumor suppressor Lijun Wang a, b, Yu-Shiuan Wang c, Eko Mugiyanto c, Wei-Chiao Chang c, d, * Yu-Jui Yvonne Wan a, a Department of Pathology and Laboratory Medicine, University of California Davis, Sacramento, CA b The College of Life Science, Yangtze University, Jingzhou, Hubei c PhD Program in Clinical Drug Development of Chinese Herbal Medicine, College of Pharmacy, Taipei Medical University, Taipei d Department of Clinical Pharmacy, School of Pharmacy, Taipei Medical University, Taipei article info abstract Article history: With obesity rate consistently increasing, a strong relationship between obesity and fatty liver disease Received 1 April 2020 has been discovered. More than 90% of bariatric surgery patients also have non-alcoholic fatty liver Received in revised form diseases (NAFLDs). NAFLD and non-alcoholic steatohepatitis (NASH), which are the hepatic manifesta- 21 May 2020 tions of metabolic syndrome, can lead to liver carcinogenesis. Unfortunately, there is no effective Accepted 1 June 2020 medicine that can be used to treat NASH or liver cancer.
    [Show full text]
  • Short-Range Repression Permits Multiple Enhancers to Function Autonomously Within a Complex Promoter
    Downloaded from genesdev.cshlp.org on October 6, 2021 - Published by Cold Spring Harbor Laboratory Press Short-range repression permits multiple enhancers to function autonomously within a complex promoter Susan Gray, Paul Szymanski, and Michael Levine Department of Biology, Center for Molecular Genetics, University of California at San Diego, La Jolla, California 92093-0322 USA Transcriptional repressors play a key role in establishing localized patterns of gene expression in the early Drosophila embryo. Several different modes of repression have been implicated in previous studies, including competition and direct interference with the transcription complex. Here, we present evidence for "quenching," whereby activators and repressors co-occupy neighboring sites in a target promoter, but the repressor blocks the ability of the activator to contact the transcription complex. This study centers on a zinc finger repressor, snail (sna), which represses the expression of neuroectodermal regulatory genes in the presumptive mesoderm. We show that sna can mediate efficient repression when bound 50-100 bp from upstream activator sites. Repression does not depend on proximity of sna-binding sites to the transcription initiation site. sna is not a dedicated repressor but, instead, appears to block disparate activators. We discuss the importance of quenching as a means of permitting separate enhancers to function autonomously within a complex promoter. [Key Words: Transcriptional repressors; gene expression; Drosophila embryo; quenching; enhancers; complex promoter] Received May 16, 1994; revised version accepted June 15, 1994. Transcriptional repression is essential for the establish- to "silencing" (Ip et al. 1991; Huang et al. 1993; Jiang et ment of localized patterns of gene expression in the al.
    [Show full text]
  • From Sequence to Information
    Preprints (www.preprints.org) | NOT PEER-REVIEWED | Posted: 22 November 2019 doi:10.20944/preprints201911.0252.v1 From Sequence to Information 1 1 1;2 Ovidiu Popa , Ellen Oldenburg and Oliver Ebenh¨oh 1 Institute of Quantitative and Theoretical Biology, Heinrich-Heine University Dusseldorf¨ 2 Cluster of Excellence on Plant Sciences, CEPLAS Abstract: Today massive amounts of sequenced metagenomic and transcriptomic data from different ecological niches and environmental locations are available. Scientific progress depends critically on methods that allow extracting useful information from the various types of sequence data. Here, we will first discuss types of information contained in the various flavours of biological sequence data, and how this information can be interpreted to increase our scientific knowledge and understanding. We argue that a mechanistic understanding is required to consistently interpret experimental observations, and that this understanding is greatly facilitated by the generation and analysis of dynamic mathematical models. We conclude that, in order to construct mathematical models and to test mechanistic hypotheses, time-series data is of critical importance. We review diverse techniques to analyse time-series data and discuss various approaches by which time-series of biological sequence data was successfully used to de-rive and test mechanistic hypotheses. Analysing the bottlenecks of current strategies in the extraction of knowledge and understanding from data, we conclude that combined experimental and theoretical efforts should be implemented as early as possible during the planning phase of individual experiments and scientific research projects. Keywords: data; sequence; information; entropy; genome; gene; proteins; time-series; modeling; meta-genomics; transcriptomics; proteomics; bioinformatics; DNA 1 Introduction When discussing the process of generating useful information from sequences, it is helpful to agree on some basic definitions.
    [Show full text]