DOCSLIB.ORG

Differential Requirements for Tcf1 Long Isoforms in CD8+ and CD4+ T Cell Responses to Acute Viral Infection

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
Differential Requirements for Tcf1 Long Isoforms in CD8+ and CD4+ T Cell Responses to Acute Viral Infection Differential Requirements for Tcf1 Long Isoforms in CD8 + and CD4+ T Cell Responses to Acute Viral Infection This information is current as Jodi A. Gullicksrud, Fengyin Li, Shaojun Xing, Zhouhao of September 26, 2021. Zeng, Weiqun Peng, Vladimir P. Badovinac, John T. Harty and Hai-Hui Xue J Immunol 2017; 199:911-919; Prepublished online 26 June 2017; doi: 10.4049/jimmunol.1700595 Downloaded from http://www.jimmunol.org/content/199/3/911 Supplementary http://www.jimmunol.org/content/suppl/2017/06/24/jimmunol.170059 Material 5.DCSupplemental http://www.jimmunol.org/ References This article cites 40 articles, 11 of which you can access for free at: http://www.jimmunol.org/content/199/3/911.full#ref-list-1 Why The JI? Submit online. • Rapid Reviews! 30 days* from submission to initial decision by guest on September 26, 2021 • No Triage! Every submission reviewed by practicing scientists • Fast Publication! 4 weeks from acceptance to publication *average 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 © 2017 by The American Association of Immunologists, Inc. All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. The Journal of Immunology Differential Requirements for Tcf1 Long Isoforms in CD8+ and CD4+ T Cell Responses to Acute Viral Infection Jodi A. Gullicksrud,*,† Fengyin Li,* Shaojun Xing,* Zhouhao Zeng,‡ Weiqun Peng,‡ Vladimir P. Badovinac,*,†,x John T. Harty,*,† and Hai-Hui Xue*,† In response to acute viral infection, activated naive T cells give rise to effector T cells that clear the pathogen and memory T cells that persist long-term and provide heightened protection. T cell factor 1 (Tcf1) is essential for several of these differentiation processes. Tcf1 is expressed in multiple isoforms, with all isoforms sharing the same HDAC and DNA-binding domains and the long isoforms containing a unique N-terminal b-catenin–interacting domain. In this study, we specifically ablated Tcf1 long isoforms in mice, while retaining expression of Tcf1 short isoforms. During CD8+ T cell responses, Tcf1 long isoforms were dispensable for generating cytotoxic CD8+ effector T cells and maintaining memory CD8+ T cell pool size, but they contributed to optimal maturation of central memory CD8+ T cells and their optimal secondary expansion in a recall response. In contrast, Tcf1 long Downloaded from isoforms were required for differentiation of T follicular helper (TFH) cells, but not TH1 effectors, elicited by viral infection. Although Tcf1 short isoforms adequately supported Bcl6 and ICOS expression in TFH cells, Tcf1 long isoforms remained important for suppressing the expression of Blimp1 and TH1-associated genes and for positively regulating Id3 to restrain germinal center TFH cell differentiation. Furthermore, formation of memory TH1 and memory TFH cells strongly depended on Tcf1 long isoforms. These data reveal that Tcf1 long and short isoforms have distinct, yet complementary, functions and may represent an evolutionarily conserved means to ensure proper programming of CD8+ and CD4+ T cell responses to viral http://www.jimmunol.org/ infection. The Journal of Immunology, 2017, 199: 911–919. n response to a viral infection, naive T cells that recognize T cells predominantly differentiate into two types of effectors: their cognate Ags become activated, expand prolifically, and TH1 cells that secrete IFN-g and enhance the cytotoxicity of ef- + differentiate into effector T cells equipped with diverse fector CD8 T cells, and T follicular helper (TFH) cells that secrete I + functions. Effector CD8 T cells acquire cytotoxic functions and IL-4 and IL-21 and provide essential help to Ab-producing B cells eliminate virus-infected cells (1, 2). In contrast, activated CD4+ (3–5). Effector T cells are heterogeneous and contain subsets that have different kinetics of contraction following the peak responses by guest on September 26, 2021 and, hence, different potential to give rise to memory T cells. *Department of Microbiology, University of Iowa, Iowa City, IA 52242; Although memory CD8+ T cells are more durable than memory † Interdisciplinary Immunology Graduate Program, University of Iowa, Iowa City, CD4+ T cells, both populations contribute to enhanced responses IA 52242; ‡Department of Physics, The George Washington University, Washington, DC 20052; and xDepartment of Pathology, Carver College of Medicine, University of upon rechallenge with the same Ag. Iowa, Iowa City, IA 52242 Differentiation of effector T cells and their transition to memory ORCIDs: 0000-0003-0777-2196 (S.X.); 0000-0003-3180-2439 (V.P.B.); 0000-0001- T cells are coordinated by transcriptional regulators (5, 6). In 7266-2802 (J.T.H.); 0000-0002-9163-7669 (H.-H.X.). activated CD8+ T cells, T-bet and Blimp1 transcription factors, as Received for publication January 6, 2017. Accepted for publication June 7, 2017. well as the Id2 cofactor, are potently induced and critically reg- This work was supported by the National Institute of Health (Grants AI112579 and ulate CD8+ effector cell differentiation and acquisition of cyto- AI115149 to H.-H.X., Grant AI042767 to J.T.H., Grant AI119160 to H.-H.X. and V.P.B., Grants AI114543 and GM113961 to V.P.B., Grant AI121080 to H.-H.X. and W.P., toxic functions (7–9). In contrast, Eomes, Bcl6, and Id3 promote and Grant AI113806 to W.P.) and the U.S. Department of Veterans Affairs (Grant I01 the transition and survival of memory CD8+ T cells (9–11). In BX002903 to H.-H.X.). J.A.G. is the recipient of a University of Iowa Presidential + Graduate Research Fellowship, a T32 Predoctoral Training Grant in Immunology CD4 T cells, T-bet and Bcl6 are the lineage-specifying master (AI007485), and the Ballard and Seashore Dissertation Fellowship. The flow cytom- regulators for TH1 and TFH cells, respectively (3, 4), and induction etry core facility at the University of Iowa is supported by the Carver College of of Blimp1 and Id2 favors T 1 differentiation at the expense of the Medicine, the Holden Comprehensive Cancer Center, and the Iowa City Veteran’s H Administration Medical Center, as well as by grants from the National Cancer Insti- TFH lineage (12, 13). In contrast to advances in elucidating the tute (P30CA086862) and the National Center for Research Resources, National transcriptional networks in CD4+ lineage differentiation at the ef- Institutes of Health (S10 OD016199). fector phase, little is known about transcriptional regulation in- The RNA sequencing data presented in this article have been submitted to the Gene + Expression Omnibus (https://www.ncbi.nlm.nih.gov/geo/) under accession number volved in memory CD4 T cell formation and functions. GSE98347. T cell factor 1 (Tcf1) has been known as a transcription factor Address correspondence and reprint requests to Dr. Hai-Hui Xue, University of Iowa, acting downstream of the Wnt pathway and can interact with 51 Newton Road, BSB 3-772, Iowa City, IA 52242. E-mail address: hai-hui-xue@uiowa. b-catenin coactivator. b-catenin is posttranslationally regulated edu and stabilized by Wnt- or PG-derived signals. In addition to its The online version of this article contains supplemental material. essential role for T cell development (14, 15), recent studies have Abbreviations used in this article: dpi, day postinfection; GC, germinal center; revealed that Tcf1 critically regulates mature T cell responses. LCMV, lymphocytic choriomeningitis virus; LCMV-Arm, LCMV Armstrong strain; LCMV-Cl13, LCMV clone 13; LN, lymph node; RNA-Seq, RNA sequencing; Tcf1, Although loss of Tcf1 modestly diminished production of effector + T cell factor 1; TCM, central memory T; TEM, effector memory T; TFH, T follicular CD8 T cells, Tcf1 is essential for maturation, longevity, and helper; WT, wild-type. secondary expansion of memory CD8+ T cells (16, 17). In acti- + Copyright Ó 2017 by The American Association of Immunologists, Inc. 0022-1767/17/$30.00 vated CD4 T cells, Tcf1 appears to restrain TH1 differentiation www.jimmunol.org/cgi/doi/10.4049/jimmunol.1700595 912 Tcf1 LONG ISOFORMS IN MATURE T CELL RESPONSES + 3 4 + + in vitro (18) but is essential for activating the TFH program by characterization of CD8 T cell responses, 2 10 Va2 P14 CD8 + acting upstream of Bcl6 (12, 19, 20). As a result of differential T cells were injected i.v. into CD45.1 B6.SJL recipient mice and infected 3 5 promoter usage and alternative splicing, multiple Tcf1 isoforms can i.p. with 2 10 PFU lymphocytic choriomeningitis virus (LCMV) Armstrong strain (LCMV-Arm). For characterization of CD4+ T cell re- be detected in T cells (21). All isoforms contain a C-terminal HMG sponses, 2 3 105 Va2+ SMARTA CD4+ T cells were injected i.v. into DNA-binding domain, which can also interact with Groucho/ CD45.1+ hosts and infected similarly. For examining CD4+ T cell re- 2 2 2 transducin-like enhancer of split corepressor proteins, and a sponses under a competitive condition, 5000 p45+/ or p45 / SMARTA + newly discovered HDAC domain (22). The Tcf1 long isoforms (p45 CD4 T cells were mixed with the same number of wild-type (WT) CD45.1+CD45.2+ SMARTA CD4+ T cells and adoptively transferred. and p42) contain an N-terminal b-catenin–binding domain, whereas At $40 d postinfection (dpi), the immune mice were infected i.v. with 2 3 the Tcf1 short isoforms (p33 and p30) lack this domain and, hence, 106 PFU LCMV clone 13 (LCMV-Cl13) to elicit secondary CD8+ or CD4+ cannot interact with b-catenin.
Load more

Recommended publications
  • RNA-Binding Protein Hnrnpll Regulates Mrna Splicing and Stability During B-Cell to Plasma-Cell Differentiation
    RNA-binding protein hnRNPLL regulates mRNA splicing and stability during B-cell to plasma-cell differentiation Xing Changa,b, Bin Lic, and Anjana Raoa,b,d,e,1 Divisions of aSignaling and Gene Expression and cVaccine Discovery, La Jolla Institute for Allergy and Immunology, La Jolla, CA 92037; bSanford Consortium for Regenerative Medicine, La Jolla, CA 92037; and dDepartment of Pharmacology and eMoores Cancer Center, University of California at San Diego, La Jolla, CA 92093 Contributed by Anjana Rao, December 2, 2014 (sent for review July 20, 2014) Posttranscriptional regulation is a major mechanism to rewire the RBP-binding sites, thus validating the specificity of RBP binding transcriptomes during differentiation. Heterogeneous nuclear to coprecipitating RNAs and mapping RBP-binding sites on the RNA-binding protein LL (hnRNPLL) is specifically induced in terminally validated RNAs at close to single-nucleotide resolution (8). differentiated lymphocytes, including effector T cells and plasma Heterogeneous nuclear RNA-binding proteins (hnRNPs) is cells. To study the molecular functions of hnRNPLL at a genome- the term applied to a collection of unrelated nuclear RBPs. wide level, we identified hnRNPLL RNA targets and binding sites in hnRNPLL was identified through a targeted lentiviral shRNA plasma cells through integrated Photoactivatable-Ribonucleoside- screen for regulators of CD45RA to CD45RO switching during Enhanced Cross-Linking and Immunoprecipitation (PAR-CLIP) and memory T-cell development (9) and independently through RNA sequencing. hnRNPLL preferentially recognizes CA dinucleo- two separate screens performed by different groups for exclusion tide-containing sequences in introns and 3′ untranslated regions of CD45 exon 4 in a minigene context (10) and for altered CD44 (UTRs), promotes exon inclusion or exclusion in a context-dependent and CD45R expression on T cells in N-ethyl-N-nitrosourea manner, and stabilizes mRNA when associated with 3′ UTRs.
    [Show full text]
  • TGF-Β1 Signaling Targets Metastasis-Associated Protein 1, a New Effector in Epithelial Cells
    Oncogene (2011) 30, 2230–2241 & 2011 Macmillan Publishers Limited All rights reserved 0950-9232/11 www.nature.com/onc ORIGINAL ARTICLE TGF-b1 signaling targets metastasis-associated protein 1, a new effector in epithelial cells SB Pakala1, K Singh1,3, SDN Reddy1, K Ohshiro1, D-Q Li1, L Mishra2 and R Kumar1 1Department of Biochemistry and Molecular Biology and Institute of Coregulator Biology, The George Washington University Medical Center, Washington, DC, USA and 2Department of Gastroenterology, Hepatology and Nutrition, The University of Texas MD Anderson Cancer Center, Houston, TX, USA In spite of a large number of transforming growth factor b1 gene chromatin in response to upstream signals. The (TGF-b1)-regulated genes, the nature of its targets with TGF-b1-signaling is largely mediated by Smad proteins roles in transformation continues to be poorly understood. (Massague et al., 2005) where Smad2 and Smad3 are Here, we discovered that TGF-b1 stimulates transcription phosphorylated by TGF-b1-receptors and associate with of metastasis-associated protein 1 (MTA1), a dual master the common mediator Smad4, which translocates to the coregulator, in epithelial cells, and that MTA1 status is a nucleus to participate in the expression of TGF-b1-target determinant of TGF-b1-induced epithelial-to-mesenchymal genes (Deckers et al., 2006). Previous studies have shown transition (EMT) phenotypes. In addition, we found that that CUTL1, also known as CDP (CCAAT displacement MTA1/polymerase II/activator protein-1 (AP-1) co-activator protein), a target of TGF-b1, is needed for its short-term complex interacts with the FosB-gene chromatin and stimu- effects of TGF-b1 on cell motility involving Smad4- lates its transcription, and FosB in turn, utilizes FosB/histone dependent pathway (Michl et al.,2005).
    [Show full text]
  • 2017.08.28 Anne Barry-Reidy Thesis Final.Pdf
    REGULATION OF BOVINE β-DEFENSIN EXPRESSION THIS THESIS IS SUBMITTED TO THE UNIVERSITY OF DUBLIN FOR THE DEGREE OF DOCTOR OF PHILOSOPHY 2017 ANNE BARRY-REIDY SCHOOL OF BIOCHEMISTRY & IMMUNOLOGY TRINITY COLLEGE DUBLIN SUPERVISORS: PROF. CLIONA O’FARRELLY & DR. KIERAN MEADE TABLE OF CONTENTS DECLARATION ................................................................................................................................. vii ACKNOWLEDGEMENTS ................................................................................................................... viii ABBREVIATIONS ................................................................................................................................ix LIST OF FIGURES............................................................................................................................. xiii LIST OF TABLES .............................................................................................................................. xvii ABSTRACT ........................................................................................................................................xix Chapter 1 Introduction ........................................................................................................ 1 1.1 Antimicrobial/Host-defence peptides ..................................................................... 1 1.2 Defensins................................................................................................................. 1 1.3 β-defensins .............................................................................................................
    [Show full text]
  • Open Dogan Phdthesis Final.Pdf
    The Pennsylvania State University The Graduate School Eberly College of Science ELUCIDATING BIOLOGICAL FUNCTION OF GENOMIC DNA WITH ROBUST SIGNALS OF BIOCHEMICAL ACTIVITY: INTEGRATIVE GENOME-WIDE STUDIES OF ENHANCERS A Dissertation in Biochemistry, Microbiology and Molecular Biology by Nergiz Dogan © 2014 Nergiz Dogan Submitted in Partial Fulfillment of the Requirements for the Degree of Doctor of Philosophy August 2014 ii The dissertation of Nergiz Dogan was reviewed and approved* by the following: Ross C. Hardison T. Ming Chu Professor of Biochemistry and Molecular Biology Dissertation Advisor Chair of Committee David S. Gilmour Professor of Molecular and Cell Biology Anton Nekrutenko Professor of Biochemistry and Molecular Biology Robert F. Paulson Professor of Veterinary and Biomedical Sciences Philip Reno Assistant Professor of Antropology Scott B. Selleck Professor and Head of the Department of Biochemistry and Molecular Biology *Signatures are on file in the Graduate School iii ABSTRACT Genome-wide measurements of epigenetic features such as histone modifications, occupancy by transcription factors and coactivators provide the opportunity to understand more globally how genes are regulated. While much effort is being put into integrating the marks from various combinations of features, the contribution of each feature to accuracy of enhancer prediction is not known. We began with predictions of 4,915 candidate erythroid enhancers based on genomic occupancy by TAL1, a key hematopoietic transcription factor that is strongly associated with gene induction in erythroid cells. Seventy of these DNA segments occupied by TAL1 (TAL1 OSs) were tested by transient transfections of cultured hematopoietic cells, and 56% of these were active as enhancers. Sixty-six TAL1 OSs were evaluated in transgenic mouse embryos, and 65% of these were active enhancers in various tissues.
    [Show full text]
  • Transcriptional Control of Tissue-Resident Memory T Cell Generation
    Transcriptional control of tissue-resident memory T cell generation Filip Cvetkovski Submitted in partial fulfillment of the requirements for the degree of Doctor of Philosophy in the Graduate School of Arts and Sciences COLUMBIA UNIVERSITY 2019 © 2019 Filip Cvetkovski All rights reserved ABSTRACT Transcriptional control of tissue-resident memory T cell generation Filip Cvetkovski Tissue-resident memory T cells (TRM) are a non-circulating subset of memory that are maintained at sites of pathogen entry and mediate optimal protection against reinfection. Lung TRM can be generated in response to respiratory infection or vaccination, however, the molecular pathways involved in CD4+TRM establishment have not been defined. Here, we performed transcriptional profiling of influenza-specific lung CD4+TRM following influenza infection to identify pathways implicated in CD4+TRM generation and homeostasis. Lung CD4+TRM displayed a unique transcriptional profile distinct from spleen memory, including up-regulation of a gene network induced by the transcription factor IRF4, a known regulator of effector T cell differentiation. In addition, the gene expression profile of lung CD4+TRM was enriched in gene sets previously described in tissue-resident regulatory T cells. Up-regulation of immunomodulatory molecules such as CTLA-4, PD-1, and ICOS, suggested a potential regulatory role for CD4+TRM in tissues. Using loss-of-function genetic experiments in mice, we demonstrate that IRF4 is required for the generation of lung-localized pathogen-specific effector CD4+T cells during acute influenza infection. Influenza-specific IRF4−/− T cells failed to fully express CD44, and maintained high levels of CD62L compared to wild type, suggesting a defect in complete differentiation into lung-tropic effector T cells.
    [Show full text]
  • Cross-Family Dimerization of Transcription Factors Fos/Jun
    Proc. Nati. Acad. Sci. USA Vol. 88, pp. 3720-3724, May 9, 1991 Biochemistry Cross-family dimerization of transcription factors Fos/Jun and ATF/CREB alters DNA binding specificity (gene regulation/oncogenes/leucine zipper/protein dimerization/transcription) TSONWIN HAI*t AND ToM CURRANt of Medical Biochemistry and Ohio State Biotechnology Center, Ohio State University, 1060 Carmack Road, Columbus, OH 43210; and tDepartment*Department of Molecular Oncology and Virology, Roche Institute of Molecular Biology, Roche Research Center, Nutley, NJ 07110 Communicated by Herbert Weissbach, January 31, 1991 ABSTRACT The Fos/Jun and ATF/CREB families of Table 1. Mammalian Fos/Jun and ATF/CREB families transcription factors function in coupling extracellular signals Family Subfamily Gene(s) to alterations in expression of specific target genes. Like many eukaryotic transcription factors, these proteins bind to DNA as Fos/Jun Fos fos, fra-), fra-2, fosB dimers. Dimerization is mediated by a structure known as the Jun c-jun, junB, junD "leucine-zipper" motif. Although Fos/Jun and ATF/CREB ATF/CREB CREB CREB, ATF-I were previously thought to interact preferentially with differ- CRE-BP1 CRE-BPI, ATF-a ent DNA regulatory elements (the AP-1/TRE and ATF/CRE ATF-3 ATF-3* sites, respectively), we rind that members of these two families ATF-4 ATF4* form selective cross-family heterodimers. The resulting het- Alternative names for CRE-BPI are ATF-2 and HB16. ACREB is erodimers display distinguishable DNA binding speclfcities a spliced variant ofCREB, ATF-aA is a spliced variant ofATF-a, and from each other and from their parental homodimers.
    [Show full text]
  • Single-Cell RNA Sequencing Analysis of Human Neural Grafts Revealed Unexpected Cell Type Underlying the Genetic Risk of Parkinson’S Disease
    Single-cell RNA Sequencing Analysis of Human Neural Grafts Revealed Unexpected Cell Type Underlying the Genetic Risk of Parkinson’s Disease Yingshan Wang1, Gang Wu2 1 Episcopal High School, 1200 N Quaker Ln, Alexandria, VA, USA, 22302 2 Fujian Sanbo Funeng Brain Hospital; Sanbo Brain Hospital Capital Medical University Abstract Parkinson’s disease (PD) is the second most common neurodegenerative disorder, affecting more than 6 million patients globally. Though previous studies have proposed several disease-related molecular pathways, how cell-type specific mechanisms contribute to the pathogenesis of PD is still mostly unknown. In this study, we analyzed single-cell RNA sequencing data of human neural grafts transplanted to the midbrains of rat PD models. Specifically, we performed cell-type identification, risk gene screening, and co-expression analysis. Our results revealed the unexpected genetic risk of oligodendrocytes as well as important pathways and transcription factors in PD pathology. The study may provide an overarching framework for understanding the cell non- autonomous effects in PD, inspiring new research hypotheses and therapeutic strategies. Keywords Parkinson’s Disease; Single-cell RNA Sequencing; Oligodendrocytes; Cell Non-autonomous; Co- expression Analysis; Transcription Factors 1 Table of Contents 1. Introduction ................................................................................................................................. 3 2. Methods......................................................................................................................................
    [Show full text]
  • Neurobiological Functions of the Period Circadian Clock 2 Gene, Per2
    Review Biomol Ther 26(4), 358-367 (2018) Neurobiological Functions of the Period Circadian Clock 2 Gene, Per2 Mikyung Kim, June Bryan de la Peña, Jae Hoon Cheong and Hee Jin Kim* Department of Pharmacy, Uimyung Research Institute for Neuroscience, Sahmyook University, Seoul 01795, Republic of Korea Abstract Most organisms have adapted to a circadian rhythm that follows a roughly 24-hour cycle, which is modulated by both internal (clock-related genes) and external (environment) factors. In such organisms, the central nervous system (CNS) is influenced by the circadian rhythm of individual cells. Furthermore, the period circadian clock 2 (Per2) gene is an important component of the circadian clock, which modulates the circadian rhythm. Per2 is mainly expressed in the suprachiasmatic nucleus (SCN) of the hypothalamus as well as other brain areas, including the midbrain and forebrain. This indicates that Per2 may affect various neurobiological activities such as sleeping, depression, and addiction. In this review, we focus on the neurobiological functions of Per2, which could help to better understand its roles in the CNS. Key Words: Circadian rhythm, Per2 gene, Sleep, Depression, Addiction, Neurotransmitter INTRODUCTION and lives in organisms because it can impart effects from the level of cells to organs including the brain. Thus, it is neces- A circadian rhythm is any physiological process that displays sary to understand clock-related genes that are controlling the a roughly 24 hour cycle in living beings, such as mammals, circadian rhythm endogenously. plants, fungi and cyanobacteria (Albrecht, 2012). In organ- The Period2 (Per2) gene is a member of the Period family isms, most biological functions such as sleeping and feeding of genes consisting of Per1, Per2, and Per3, and is mainly patterns are adapted to the circadian rhythm.
    [Show full text]
  • Fosb Induction in Nucleus Accumbens by Cocaine Is Regulated by E2f3a
    New Research Disorders of the Nervous System Fosb Induction in Nucleus Accumbens by Cocaine Is Regulated by E2F3a Hannah M. Cates,1 Casey K. Lardner,1 Rosemary C. Bagot,1 Rachael L. Neve,2 and Eric J. Nestler1 https://doi.org/10.1523/ENEURO.0325-18.2019 1Nash Family Department of Neuroscience and Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, New York 10029 and 2Gene Delivery Technology Core, Massachusetts General Hospital, Cambridge, Massachusetts 02139 Abstract The transcription factor ⌬FosB has been proposed as a molecular switch for the transition from casual, volitional drug use into a chronically addicted state, but the upstream regulatory mechanisms governing ⌬FosB expression are incompletely understood. In this study, we find a novel regulatory role for the transcription factor E2F3, recently implicated in transcriptional regulation by cocaine, in controlling ⌬FosB induction in the mouse nucleus accumbens (NAc) following cocaine administration. We find that an E2F consensus sequence 500 bp upstream of the Fosb transcription start site is enriched for E2F3 specifically over other E2F isoforms. We further conclude that ⌬FosB expression is regulated specifically by E2F3a, not E2F3b, that E2f3a expression is specific to D1 receptor-expressing medium spiny neurons, and that E2F3a overexpression in NAc recapitulates the induction of Fosb and ⌬Fosb mRNA expression observed after chronic cocaine exposure. E2F3a knockdown in NAc does not abolish ⌬Fosb induction by cocaine, a result consistent with previously published data showing that singular knockdown of upstream regulators of ⌬FosB is insufficient to block cocaine-induced expression. Finally, to elucidate potential combinatorial epigenetic mechanisms involved in E2F3a’s regulation of Fosb, we explore H3K4me3 enrichment at the Fosb promoter and find that it is not enhanced by E2F3a overexpression, suggesting that it may instead be a pre-existing permissive mark allowing for E2F3a to interact with Fosb.
    [Show full text]
  • BCL6 Repression of EP300 in Human Diffuse Large B Cell Lymphoma Cells Provides a Basis for Rational Combinatorial Therapy Leandro C
    Research article BCL6 repression of EP300 in human diffuse large B cell lymphoma cells provides a basis for rational combinatorial therapy Leandro C. Cerchietti,1,2 Katerina Hatzi,1,2 Eloisi Caldas-Lopes,3 Shao Ning Yang,1,2 Maria E. Figueroa,1,2 Ryan D. Morin,4 Martin Hirst,4 Lourdes Mendez,1 Rita Shaknovich,5 Philip A. Cole,6 Kapil Bhalla,7 Randy D. Gascoyne,8 Marco Marra,4 Gabriela Chiosis,3 and Ari Melnick1,2 1Hematology and Oncology Division, and 2Department of Pharmacology, Weill Cornell Medical College, New York, New York, USA. 3Department of Molecular Pharmacology and Chemistry, Sloan-Kettering Institute, New York, New York, USA. 4Genome Sciences Centre, British Columbia Cancer Agency, Vancouver, British Columbia, Canada. 5Department of Pathology, Weill Cornell Medical College, New York, New York, USA. 6Department of Pharmacology and Molecular Sciences, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA. 7The University of Kansas Cancer Center, Kansas University Medical Center, Kansas City, Kansas, USA. 8Centre for Lymphoid Cancers and the Departments of Pathology and Experimental Therapeutics, British Columbia Cancer Agency, British Columbia Cancer Research Centre, Vancouver, British Columbia, Canada. B cell lymphoma 6 (BCL6), which encodes a transcriptional repressor, is a critical oncogene in diffuse large B cell lymphomas (DLBCLs). Although a retro-inverted BCL6 peptide inhibitor (RI-BPI) was recently shown to potently kill DLBCL cells, the underlying mechanisms remain unclear. Here, we show that RI-BPI induces a particular gene expression signature in human DLBCL cell lines that included genes associated with the actions of histone deacetylase (HDAC) and Hsp90 inhibitors.
    [Show full text]
  • AP-1 in Cell Proliferation and Survival
    Oncogene (2001) 20, 2390 ± 2400 ã 2001 Nature Publishing Group All rights reserved 0950 ± 9232/01 $15.00 www.nature.com/onc AP-1 in cell proliferation and survival Eitan Shaulian1 and Michael Karin*,1 1Laboratory of Gene Regulation and Signal Transduction, Department of Pharmacology, University of California San Diego, 9500 Gilman Drive, La Jolla, California, CA 92093-0636, USA A plethora of physiological and pathological stimuli extensively discussed previously (Angel and Karin, induce and activate a group of DNA binding proteins 1991; Karin, 1995). that form AP-1 dimers. These proteins include the Jun, The mammalian AP-1 proteins are homodimers and Fos and ATF subgroups of transcription factors. Recent heterodimers composed of basic region-leucine zipper studies using cells and mice de®cient in individual AP-1 (bZIP) proteins that belong to the Jun (c-Jun, JunB proteins have begun to shed light on their physiological and JunD), Fos (c-Fos, FosB, Fra-1 and Fra-2), Jun functions in the control of cell proliferation, neoplastic dimerization partners (JDP1 and JDP2) and the closely transformation and apoptosis. Above all such studies related activating transcription factors (ATF2, LRF1/ have identi®ed some of the target genes that mediate the ATF3 and B-ATF) subfamilies (reviewed by (Angel eects of AP-1 proteins on cell proliferation and death. and Karin, 1991; Aronheim et al., 1997; Karin et al., There is evidence that AP-1 proteins, mostly those that 1997; Liebermann et al., 1998; Wisdom, 1999). In belong to the Jun group, control cell life and death addition, some of the Maf proteins (v-Maf, c-Maf and through their ability to regulate the expression and Nrl) can heterodimerize with c-Jun or c-Fos (Nishiza- function of cell cycle regulators such as Cyclin D1, p53, wa et al., 1989; Swaroop et al., 1992), whereas other p21cip1/waf1, p19ARF and p16.
    [Show full text]
  • Supplement. Transcriptional Factors (TF), Protein Name and Their Description Or Function
    Supplement. Transcriptional factors (TF), protein name and their description or function. TF Protein name TF description/function ARID3A AT rich interactive domain 3A (BRIGHT-like) This gene encodes a member of the ARID (AT-rich interaction domain) family of DNA binding proteins. ATF4 Activating Transcription Factor 4 Transcriptional activator. Binds the cAMP response element (CRE) (consensus: 5-GTGACGT[AC][AG]-3), a sequence present in many viral and cellular promoters. CTCF CCCTC-Binding Factor Chromatin binding factor that binds to DNA sequence specific sites. Involved in transcriptional regulation by binding to chromatin insulators and preventing interaction between promoter and nearby enhancers and silencers. The protein can bind a histone acetyltransferase (HAT)-containing complex and function as a transcriptional activator or bind a histone deacetylase (HDAC)-containing complex and function as a transcriptional repressor. E2F1-6 E2F transcription factors 1-6 The protein encoded by this gene is a member of the E2F family of transcription factors. The E2F family plays a crucial role in the control of cell cycle and action of tumor suppressor proteins and is also a target of the transforming proteins of small DNA tumor viruses. The E2F proteins contain several evolutionally conserved domains found in most members of the family. These domains include a DNA binding domain, a dimerization domain which determines interaction with the differentiation regulated transcription factor proteins (DP), a transactivation domain enriched in acidic amino acids, and a tumor suppressor protein association domain which is embedded within the transactivation domain. EBF1 Transcription factor COE1 EBF1 has been shown to interact with ZNF423 and CREB binding proteins.
    [Show full text]