DOCSLIB.ORG

Transcription Coactivators and Corepressors

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
Transcription Coactivators and Corepressors EXPERIMENTAL and MOLECULAR MEDICINE, Vol. 32, No. 2, 53-60, June 2000 Dissecting the molecular mechanism of nuclear receptor action: transcription coactivators and corepressors Jae Woon Lee1,2,4, JaeHun Cheong1,2, nucleosomal remodeling histone acetyl transferase (HAT) Young Chul Lee1,2, Soon-Young Na1,3 or deacetylase (HDAC) activities. Thus, these proteins and Soo-Kyung Lee1,3 appear to function by either remodeling chromatin struc- tures and/or acting as adapter molecules between nu- clear receptors and the components of the basal trans- 1 Center for Ligand and Transcription criptional apparatus. Herein, we discuss the recent pro- 2 Hormone Research Center gress in studies of these coactivators and corepressors 3 Department of Biology, Chonnam National University, of nuclear receptors. Kwangju 500-757, Korea 4 Corresponding author: Tel, +82-62-530-0910; Fax, +82-62-530-0772; E-mail, [email protected] The p160 Family Accepted 21 June 2000 A group of related proteins were found to enhance Abbreviations: HRE, hormone response elements; LBD, ligand ligand-induced transactivation function of several nuclear binding domain; AF2, activation function; HAT, histone acetyl trans- receptors, named the p160 family. These proteins are ferase; HDAC, deacetylase; CBP, CREB-binding protein; TRAPs, grouped into three subclasses based on their sequence homology; i.e., SRC-1/NCoA-1 (Hong et al., 1997; Torchia thyroid homone receptor associated proteins; VDR, vitamin D3; ASC-1, activating signal cointegrator-1; RAR, retinoic acid receptor et al., 1997; Voegel et al., 1998), TIF2/GRIP1/NCoA-2 (Hong et al., 1997; Voegel et al., 1998), and p/CIP/ ACTR/AIB1/xSRC-3 (Anzick et al., 1997; Chen et al., 1997; Kim et al., 1998; Torchia et al., 1997). A distinctive Keywords: Nuclear receptor, transcription, coactivators, structural feature of the p160 coactivators is the corepressors presence of multiple LXXLL signature motifs (Heery et al., 1997; Torchia et al., 1997). The AF2 core (helix 12) was recently shown to undergo a major restructuring Introduction upon ligand binding, forming part of a “charged clamp” that accomodates p160 coactivators within a hydrophobic Over 150 members that belong to the nuclear receptor cleft of the receptor LBD, through direct contacts with superfamily have been discovered since glucocorticoid these LXXLL motifs (Darimont et al., 1998; Nolte et al., receptor was first reported in 1985, which primarily regu- 1998). Loss of function studies using antibody microin- late, in a ligand-dependent manner, transcriptional initi- jection technique also suggested that the p160 family ation of the target genes by directly binding to specific proteins are required for nuclear receptor functions in DNA sequences named hormone response elements vivo (Torchia et al., 1997). In addition, these factors can (HRE) (reviewed in Mangelsdorf et al., 1995). The C- also interact with CREB-binding protein (CBP)/p300 via terminus of the ligand binding domain (LBD) of these a separate domain (Kamei et al., 1996; Yao et al., 1996). proteins harbors an essential ligand-dependent trans- A weak intrinsic HAT activity has been reported in SRC- activation function (activation function 2, AF2), whereas 1 and ACTR, suggesting that a function of these factor the N-terminus of many nuclear receptors often includes may involve chromatin remodeling (Chen et al., 1997; AF1. Genetic studies implicated that transcription cofac- Spencer et al., 1997). We have recently shown that tors with no specific DNA-binding activity are essential SRC-1 also mediates transactivation by a series of other components of transcriptional regulation, which ultimate- transcription factors, including AP-1 (Lee et al., 1998), ly led to identify a series of nuclear receptor-interacting NFκB (Na et al., 1998), SRF (Kim et al., 1998a), and coregulatory proteins (reviewed in Horwitz et al., 1996). p53 (Lee et al., 1999). In particular, SRC-1 and p/CIP Thus far, these proteins have been shown to have a few were strong coactivators for p53, whereas AIB1 and characteristic features, as summarized in Figure 1. First, xSRC-3 were repressive (Lee et al., 1999). It is also they bind to target transcription factors in a ligand- noted that the p160 family of proteins has a number of dependent manner. Second, many of them are capable uncharacterized isoforms (Chen et al., 1997; our un- of directly interacting with the basal transcriptional published results). These results suggest a provoking machinery. Third, some of them exhibit enzymatic func- hypothesis that each member of the p160 family or iso- tion intrinsically linked to gene regulation, such as the forms may regulate a specific set of target transcription 54 Exp. Mol. Med. Vol. 32(2), 53-60, 2000 Figure 1. The role of transcriptional cofactors. Three general functions of known receptor cofactors are denoted as I, II, and III (see the text for details). HRE and +1 denote hormone response elements and transcription initiation site, respectively. Nuclear receptors, nucleosomes, cofactor and RNA polymerase II bound to TATA sequences are schematically depicted. Notably, RNA polymerase II and most cofactors exist as steady-state complex of multiple polypeptides, although each of them is represented as a single polypeptide for simplicity. factors in vivo. p/CAF This protein was first discovered on the basis of sequ- CBP/p300 ence homology to the yeast HAT protein Gcn5p (Yang et al., 1996). The N-terminus of p/CAF interacts with CBP was originally isolated on the basis of its associ- CBP and members of the p160 family, whereas inter- ation with CREB in response to cAMP signaling, where- action interface between p/CAF and nuclear receptors as its close homologue, p300, was purified as a cellular was different from that mediating the binding with either binding protein of the adenoviral protein E1A (Chrivia et CBP/p300 or p160s (Blanco et al., 1998; Korzus et al., al., 1993; Eckner et al., 1994). CBP and p300 have 1998). A core p/CAF complex was recently isolated by been implicated in functions of a large number of regu- exploiting an affinity purification approach, which contain- lated transcription factors (reviewed in Goldman et al., ed human homologues of the yeast ADA proteins, TAFs 1997). For nuclear receptors, the interaction with CBP/ or TAF homologs, and p/CAF associated factor 65α which p300 is ligand- and AF2-dependent, although this direct contains histone-like structure (Ogryzko et al., 1998). interaction does not appear to be essential with many These results suggest a possible link between the p/ nuclear receptors (Westin et al., 1998; Li et al., 2000). In CAF complex and the RNA polymerase II core machi- fibroblasts isolated from a p300−/− mouse, however, RA- nery. This p/CAF complex bears resemblance to the dependent transcription was severely impaired, clearly GCN5/SAGA complex in yeast. In particular, other sub- indicating that CBP/p300 are components of hormonal units of the complex facilitate p/CAF to acetylate his- regulation of transcription in vivo (Yao et al., 1998). tones in the context of nucleosomes, although p/CAF Surprisingly, CBP and p300 harbor HAT activity alone is inert (Grant et al., 1997). (Bannister et al., 1996; Ogryzko et al., 1996). In addition, purified p300 was shown to potentiate ligand- induced ER function only on chromatinized template, TRAP/DRIP Complexes strongly indicating that a major function of CBP/p300 could be to modify chromatin structure via histone The thyroid hormone receptor associated proteins (TRAPs), acetylation (Kraus and Kadonaga, 1998). However, it is composed of at least 9 polypeptides, were immuno- notable that CBP/p300 can also acetylate and purified from cells stably transfected with flag-tagged functionally modulate, either in a negative or positive thyroid hormone receptors (Fondell et al., 1996). In re- manner, non-histone proteins, including TFIIEβ (Imhof et constituted in vitro transcription assays utilizing naked al., 1997), p53 (Gu and Roeder, 1997), hematopoietic DNA templates, the TRAP complex potentiated trans- transcription factor GATA-1 (Boyes et al., 1998) and activation function of liganded TR. A highly homologous erythroid Krüppel-like factor (Zhang and Bieker, 1998). DRIP (vitamin D3 receptor (VDR) interacting protein) These results suggest that CBP/p300 may also target complex was also isolated using VDR as the affinity different aspects of gene activation, in addition to their matrix (Rachez et al., 1998), which substantially poten- roles in chromatin remodeling. tiated ligand-dependent transactivation function of VDR Dissecting the molecular mechanism of nuclear receptor action 55 on a chromatinized template in vitro (Rachez et al., tional coactivator, p52, interacted not only with transcrip- 1999). Interestingly, constituents of DRIP complex are tional activators and general transcription factors to almost identical to another newly discovered ARC (acti- enhance activated transcription but also with the essen- vator recruited cofactor) complex, which is essential for tial splicing factor ASF/SF2 both in vitro and in vivo to a number of other transcription factors such as SREBP, modulate ASF/SF2-mediated pre-mRNA splicing (Ge and NFκB and VP16 (Naar et al., 1999; Rachez et al., Wolfe, 1998). These results, along with the notion that 1999). This TRAP/DRIP complex is recruited to the LBD pre-mRNA splicing can take place cotranscriptionally in AF2 core in response to ligand-binding through a single vivo, suggest that, in addition to functioning as a trans- subunit (DRIP205/TRAP220/TRIP2) via a single LXXLL criptional coactivator, ASC-1 may also act as an adaptor motif (Lee et al., 1995; Naar et al., 1999; Rachez et al., to coordinate pre-mRNA splicing and transcriptional 1999). This protein anchors the other components of the activation of class II genes. DRIP/TRAP complex to the receptor, thereby conferring hormone-dependent recruitment of what appears to be a preformed complex. In addition, TRAP/DRIP/ARC also ASC-2 contain part of the “Mediator complex” (Kim et al., 1994), strongly suggesting their direct connection to the RNA Activating signal cointegrator-2 (ASC-2) is another novel polymerase II core machinery.
Load more

Recommended publications
  • Interaction and Functional Cooperation of the Cancer-Amplified Transcriptional Coactivator Activating Signal Cointegrator-2 and E2F-1 in Cell Proliferation
    948 Vol. 1, 948–958, November 2003 Molecular Cancer Research Interaction and Functional Cooperation of the Cancer-Amplified Transcriptional Coactivator Activating Signal Cointegrator-2 and E2F-1 in Cell Proliferation Hee Jeong Kong,1 Hyun Jung Yu,2 SunHwa Hong,2 Min Jung Park,2 Young Hyun Choi,3 Won Gun An,4 Jae Woon Lee,5 and JaeHun Cheong2 1Laboratory of Molecular Growth Regulation, National Institute of Health, Bethesda, MD; 2Department of Molecular Biology, Pusan National University, Busan, Republic of Korea; 3Department of Biochemistry, College of Oriental Medicine, Dong-Eui University, Busan, Republic of Korea; 4Department of Biology, Kyungpook National University, DaeGu, Republic of Korea; and 5Department of Medicine/Endocrinology, Baylor College of Medicine Houston, TX. Abstract structure and recruitment of a transcription initiation complex Activating signal cointegrator-2 (ASC-2), a novel coac- containing RNA polymerase II to the promoter (1). Recent tivator, is amplified in several cancer cells and known to studies have shown that DNA-bound transcriptional activator interact with mitogenic transcription factors, including proteins accomplish these two tasks with the assistance of a serum response factor, activating protein-1, and nuclear class of proteins called transcriptional coactivators (2, 3). They factor-KB, suggesting the physiological role of ASC-2 in may be thought of as adaptors or components in a signaling the promotion of cell proliferation. Here, we show that pathway that transmits transcriptional activation signals from the expression pattern of ASC-2 was correlated with that DNA-bound activator proteins to the chromatin and transcrip- of E2F-1 for protein increases at G1 and S phase.
    [Show full text]
  • Homeobox Gene Expression Profile in Human Hematopoietic Multipotent
    Leukemia (2003) 17, 1157–1163 & 2003 Nature Publishing Group All rights reserved 0887-6924/03 $25.00 www.nature.com/leu Homeobox gene expression profile in human hematopoietic multipotent stem cells and T-cell progenitors: implications for human T-cell development T Taghon1, K Thys1, M De Smedt1, F Weerkamp2, FJT Staal2, J Plum1 and G Leclercq1 1Department of Clinical Chemistry, Microbiology and Immunology, Ghent University Hospital, Ghent, Belgium; and 2Department of Immunology, Erasmus Medical Center, Rotterdam, The Netherlands Class I homeobox (HOX) genes comprise a large family of implicated in this transformation proces.14 The HOX-C locus transcription factors that have been implicated in normal and has been primarily implicated in lymphomas.15 malignant hematopoiesis. However, data on their expression or function during T-cell development is limited. Using degener- Hematopoietic cells are derived from stem cells that reside in ated RT-PCR and Affymetrix microarray analysis, we analyzed fetal liver (FL) in the embryo and in the adult bone marrow the expression pattern of this gene family in human multipotent (ABM), which have the unique ability to self-renew and thereby stem cells from fetal liver (FL) and adult bone marrow (ABM), provide a life-long supply of blood cells. T lymphocytes are a and in T-cell progenitors from child thymus. We show that FL specific type of hematopoietic cells that play a major role in the and ABM stem cells are similar in terms of HOX gene immune system. They develop through a well-defined order of expression, but significant differences were observed between differentiation steps in the thymus.16 Several transcription these two cell types and child thymocytes.
    [Show full text]
  • Original Article EP300 Regulates the Expression of Human Survivin Gene in Esophageal Squamous Cell Carcinoma
    Int J Clin Exp Med 2016;9(6):10452-10460 www.ijcem.com /ISSN:1940-5901/IJCEM0023383 Original Article EP300 regulates the expression of human survivin gene in esophageal squamous cell carcinoma Xiaoya Yang, Zhu Li, Yintu Ma, Xuhua Yang, Jun Gao, Surui Liu, Gengyin Wang Department of Blood Transfusion, The Bethune International Peace Hospital of China PLA, Shijiazhuang 050082, Hebei, P. R. China Received January 6, 2016; Accepted March 21, 2016; Epub June 15, 2016; Published June 30, 2016 Abstract: Survivin is selectively up-regulated in various cancers including esophageal squamous cell carcinoma (ESCC). The underlying mechanism of survivin overexpression in cancers is needed to be further studied. In this study, we investigated the effect of EP300, a well known transcriptional coactivator, on survivin gene expression in human esophageal squamous cancer cell lines. We found that overexpression of EP300 was associated with strong repression of survivin expression at the mRNA and protein levels. Knockdown of EP300 increased the survivin ex- pression as indicated by western blotting and RT-PCR analysis. Furthermore, our results indicated that transcription- al repression mediated by EP300 regulates survivin expression levels via regulating the survivin promoter activity. Chromatin immunoprecipitation (ChIP) analysis revealed that EP300 was associated with survivin gene promoter. When EP300 was added to esophageal squamous cancer cells, increased EP300 association was observed at the survivin promoter. But the acetylation level of histone H3 at survivin promoter didn’t change after RNAi-depletion of endogenous EP300 or after overexpression of EP300. These findings establish a negative regulatory role for EP300 in survivin expression. Keywords: Survivin, EP300, transcription regulation, ESCC Introduction transcription factors and the basal transcrip- tion machinery, or by providing a scaffold for Survivin belongs to the inhibitor of apoptosis integrating a variety of different proteins [6].
    [Show full text]
  • CHD7 Represses the Retinoic Acid Synthesis Enzyme ALDH1A3 During Inner Ear Development
    CHD7 represses the retinoic acid synthesis enzyme ALDH1A3 during inner ear development Hui Yao, … , Shigeki Iwase, Donna M. Martin JCI Insight. 2018;3(4):e97440. https://doi.org/10.1172/jci.insight.97440. Research Article Development Neuroscience CHD7, an ATP-dependent chromatin remodeler, is disrupted in CHARGE syndrome, an autosomal dominant disorder characterized by variably penetrant abnormalities in craniofacial, cardiac, and nervous system tissues. The inner ear is uniquely sensitive to CHD7 levels and is the most commonly affected organ in individuals with CHARGE. Interestingly, upregulation or downregulation of retinoic acid (RA) signaling during embryogenesis also leads to developmental defects similar to those in CHARGE syndrome, suggesting that CHD7 and RA may have common target genes or signaling pathways. Here, we tested three separate potential mechanisms for CHD7 and RA interaction: (a) direct binding of CHD7 with RA receptors, (b) regulation of CHD7 levels by RA, and (c) CHD7 binding and regulation of RA-related genes. We show that CHD7 directly regulates expression of Aldh1a3, the gene encoding the RA synthetic enzyme ALDH1A3 and that loss of Aldh1a3 partially rescues Chd7 mutant mouse inner ear defects. Together, these studies indicate that ALDH1A3 acts with CHD7 in a common genetic pathway to regulate inner ear development, providing insights into how CHD7 and RA regulate gene expression and morphogenesis in the developing embryo. Find the latest version: https://jci.me/97440/pdf RESEARCH ARTICLE CHD7 represses the retinoic acid synthesis enzyme ALDH1A3 during inner ear development Hui Yao,1 Sophie F. Hill,2 Jennifer M. Skidmore,1 Ethan D. Sperry,3,4 Donald L.
    [Show full text]
  • Oncjuly3 6..6
    Oncogene (1999) 18, 4137 ± 4143 ã 1999 Stockton Press All rights reserved 0950 ± 9232/99 $12.00 http://www.stockton-press.co.uk/onc Tax protein of HTLV-1 inhibits CBP/p300-mediated transcription by interfering with recruitment of CBP/p300 onto DNA element of E-box or p53 binding site Takeshi Suzuki1, Masami Uchida-Toita1 and Mitsuaki Yoshida*,1 1Department of Cellular and Molecular Biology, Institute of Medical Science, The University of Tokyo, 4-6-1 Shirokanedai, Minato-ku, Tokyo 108-8639, Japan Tax protein of human T-cell leukemia virus type 1 Tax was originally identi®ed as a transcriptional (HTLV-1) is a potent transcriptional regulator which can activator for viral gene expression and then was shown activate or repress speci®c cellular genes and has been to activate a wide variety of cellular genes (Yoshida et proposed to contribute to leukemogenic processes in al., 1995). Tax was also demonstrated to inhibit adult T-cell leukemia. The molecular mechanism of Tax- expression of several genes. In addition to the mediated trans-activation has been well investigated. transcriptional deregulation, we found that Tax binds However, trans-repression by Tax remains to be studied to p16ink4a protein, a cyclin-dependent kinase (CDK) in detail, although it is known to require a speci®c DNA inhibitor, and suppresses its inhibitory activity pre- element such as E-box or p53 binding site. Examining venting the cell from undergoing growth arrest (Suzuki possible mechanisms of trans-repression, we found that et al., 1996). These pleiotropic functions of Tax aect co-expression of E47 and p300 activated E-box multiple regulatory processes of cells and are believed dependent transcription and this activation was eciently to play roles at least in the initial stage of repressed by Tax.
    [Show full text]
  • Crystal Structure of the Bacteriophage T4 Late-Transcription Coactivator Gp33 with the Β-Subunit Flap Domain of Escherichia Coli RNA Polymerase
    Crystal structure of the bacteriophage T4 late-transcription coactivator gp33 with the β-subunit flap domain of Escherichia coli RNA polymerase The Harvard community has made this article openly available. Please share how this access benefits you. Your story matters Citation Twist, K.-A. F., E. A. Campbell, P. Deighan, S. Nechaev, V. Jain, E. P. Geiduschek, A. Hochschild, and S. A. Darst. 2011. “Crystal Structure of the Bacteriophage T4 Late-Transcription Coactivator gp33 with the -Subunit Flap Domain of Escherichia Coli RNA Polymerase.” Proceedings of the National Academy of Sciences 108 (50): 19961– 66. https://doi.org/10.1073/pnas.1113328108. Citable link http://nrs.harvard.edu/urn-3:HUL.InstRepos:41483152 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 Crystal structure of the bacteriophage T4 late- transcription coactivator gp33 with the β-subunit flap domain of Escherichia coli RNA polymerase Kelly-Anne F. Twista,1, Elizabeth A. Campbella, Padraig Deighanb, Sergei Nechaevc,2, Vikas Jainc,3, E. Peter Geiduschekc, Ann Hochschildb, and Seth A. Darsta,4 aLaboratory of Molecular Biophysics, The Rockefeller University, 1230 York Avenue, New York, NY 10065; bDepartment of Microbiology and Immunobiology, Harvard Medical School, Boston, MA 02115; and cDivision of Biological Sciences, Section of Molecular Biology, University
    [Show full text]
  • Transcrip\Onal and Epigene\C Changes During Heart Disease
    786/110 Transcrip)onal and Epigene)c Changes during Heart Disease Danish Sayed Unique Features of Heart • Involuntary, rhythmic, cyclic contractions • Terminally differentiated, postnatal myocytes increase in size not numbers for growth • Number of non myocytes (e.g. fibroblasts) is more (60-70%) compared to number of myocytes (~30%). Neonate Heart Postnatal Growth “Physiological” Adult Heart - Exercise - Hypertension - Pregnancy - Aortic Stenosis - Sarcomeric Gene mutation - Myocardial Infarction - Dilated Cardiomyopathy Physiological Pathological Hypertrophy Hypertrophy Dilatation and Failure Compensatory Decompensation Overload • Increase in cardiomyocyte size • Chamber dilatation and mass, resulting in enlarged heart • Decreased Ventricular Wall • Increase in generalized gene Thickness and Increased expression, superimposed with wall tension significant increase in specialized genes, fetal gene • Altered Ca+2 handling program • Increased wall thickness • Increased myocardial • Switch to glucose metabolism apoptosis for energy Compromised Maintained Cardiac Cardiac function and Function and Output Output Modulators of Cardiac Hypertrophy L-Type Ca+2 Ang II, ET-1 Channel α-Adrenergic β-Adrenergic Mechanical Ca+2 Insulin-like Growth Stretch + Factor Na Gq Gs P Ca+2 PKA PLC Adenylyl Integrin Cyclase Ca+2 RAS-GTP Na+ PI3K IP3 DAG cAMP Calcineurine FAK AKT Ca+2 Rho PKC PKA Ras mTOR Rac GSK3β 4EBP1 Rock MLCK NFAT MAPK eIF2B p70S6K eIF4E ME ME ME ME GATA4 GATA4 MEF2 Sarcomere SRF Translation AC AC Transcription HDAC Histone Acetylation HAT Modificatn. Methylation HMT Chromatin Demethylases Remodeling Phosphorylation DNA Methylation Transcriptional Modificatn. General Factors Transcription factors TFIIA, TFIIB, TFIID… Promoter Specific Factors GATA family, NFATc family Activity Recruitment Gene Regulation RNA Polymerase II Dynamics Initiation Elongation Translation factors e.g.
    [Show full text]
  • Repressor to Activator Switch by Mutations in the First Zn Finger of The
    Proc. Nat!. Acad. Sci. USA Vol. 88, pp. 7086-7090, August 1991 Biochemistry Repressor to activator switch by mutations in the first Zn finger of the glucocorticoid receptor: Is direct DNA binding necessary? (interleukin 1 indudbility/dexamethasone modulation/DNA-binding domain mutants/interleukin 6 and c-fos promoters) ANURADHA RAY, K. STEVEN LAFORGE, AND PRAVINKUMAR B. SEHGAL* The Rockefeller University, New York, NY 10021 Communicated by Igor Tamm, May 20, 1991 (receivedfor review March 15, 1991) ABSTRACT Transfection ofHeLa cells with cDNA vectors previous experiments in HeLa cells transfected with cDNA expressing the wild-type human glucocorticoid receptor (GR) vectors constitutively expressing the wild type (wt) but not enabled dexamethasone to strongly repress cytokine- and sec- the inactive carboxyl-terminal truncation mutants of GR, we ond messenger-induced expression of cotransfected chimeric observed that dexamethasone (Dex) strongly repressed the reporter genes containing transcription regulatory DNA ele- induction by interleukin 1 (IL-1), tumor necrosis factor, ments from the human interleukin 6 (IL-6) promoter. Deletion phorbol ester, or forskolin of IL-6-chloramphenicol acetyl- of the DNA-binding domain or of the second Zn finger or a transferase (CAT) constructs containing IL-6 DNA from point mutation in the Zn catenation site in the second finger -225 to +13. Dex also repressed induction of IL-6- blocked the ability of GR to mediate repression of the IL-6 thymidine kinase (TK)-CAT chimeric constructs containing promoter.
    [Show full text]
  • Drosophila Pax6 Promotes Development of the Entire Eye-Antennal Disc, Thereby Ensuring Proper Adult Head Formation
    PAPER Drosophila Pax6 promotes development of the entire COLLOQUIUM eye-antennal disc, thereby ensuring proper adult head formation Jinjin Zhua, Sneha Palliyila, Chen Ranb, and Justin P. Kumara,1 aDepartment of Biology, Indiana University, Bloomington, IN 47405; and bDepartment of Biology, Stanford University, Stanford, CA 94305 Edited by Ellen V. Rothenberg, California Institute of Technology, Pasadena, CA, and accepted by Editorial Board Member Neil H. Shubin February 17, 2017 (received for review July 26, 2016) Paired box 6 (Pax6) is considered to be the master control gene for molecular battle among GRNs allows for the subdivision of the eye development in all seeing animals studied so far. In vertebrates, eye-antennal disc to be maintained within a single continuous it is required not only for lens/retina formation but also for the cellular field (13–16). Of the GRNs that are known to operate development of the CNS, olfactory system, and pancreas. Although within the eye-antennal disc, the retinal determination (RD) Pax6 plays important roles in cell differentiation, proliferation, and network, which controls eye development, is the best studied (17). patterning during the development of these systems, the underlying At the core of the RD network lie the Paired box 6 (Pax6) genes mechanism remains poorly understood. In the fruit fly, Drosophila eyeless (ey)andtwin of eyeless (toy), the SIX family member sine melanogaster, Pax6 also functions in a range of tissues, including oculis (so), the transcriptional coactivator eyes absent (eya), and the the eye and brain. In this report, we describe the function of Pax6 in Ski/Sno family member dachshund (dac)(17).
    [Show full text]
  • A Thyroid Hormone Receptor Coactivator Negatively Regulated by the Retinoblastoma Protein
    Proc. Natl. Acad. Sci. USA Vol. 94, pp. 9040–9045, August 1997 Biochemistry A thyroid hormone receptor coactivator negatively regulated by the retinoblastoma protein KAI-HSUAN CHANG*†,YUMAY CHEN*†,TUNG-TI CHEN*†,WEN-HAI CHOU*†,PHANG-LANG CHEN*, YEN-YING MA‡,TERESA L. YANG-FENG‡,XIAOHUA LENG§,MING-JER TSAI§,BERT W. O’MALLEY§, AND WEN-HWA LEE*¶ *Department of Molecular Medicine and Institute of Biotechnology, University of Texas Health Science Center at San Antonio, 15355 Lambda Drive, San Antonio, TX 78245; ‡Department of Genetics, Obstetrics, and Gynecology, Yale University School of Medicine, New Haven, CT 06510; and §Department of Cell Biology, Baylor College of Medicine, Houston, TX 77030 Contributed by Bert W. O’Malley, June 9, 1997 ABSTRACT The retinoblastoma protein (Rb) plays a E2F-1, a transcription factor important for the expression of critical role in cell proliferation, differentiation, and devel- several genes involved in cell cycle progression from G1 to S opment. To decipher the mechanism of Rb function at the (18). Rb inhibits E2F-1 activity by blocking its transactivation molecular level, we have systematically characterized a num- region (19–21). In contrast, Rb has been shown to have the ber of Rb-interacting proteins, among which is the clone C5 ability to increase the transactivating activity of the members described here, which encodes a protein of 1,978 amino acids of the CCAATyenhancer binding protein (CyEBP) family, and with an estimated molecular mass of 230 kDa. The corre- to be required for CyEBPs-dependent adipocyte and mono- sponding gene was assigned to chromosome 14q31, the same cytes differentiation (16–17).
    [Show full text]
  • Identification of a Family of Camp Response Element-Binding Protein Coactivators by Genome-Scale Functional Analysis in Mammalian Cells
    Identification of a family of cAMP response element-binding protein coactivators by genome-scale functional analysis in mammalian cells Vadim Iourgenko*†, Wenjun Zhang*†, Craig Mickanin*, Ira Daly*, Can Jiang*, Jonathan M. Hexham*, Anthony P. Orth‡, Loren Miraglia‡, Jodi Meltzer*, Dan Garza*, Gung-Wei Chirn*, Elizabeth McWhinnie*, Dalia Cohen*, Joanne Skelton*, Robert Terry*, Yang Yu*, Dale Bodian*, Frank P. Buxton*, Jian Zhu*, Chuanzheng Song*, and Mark A. Labow*§ *Department of Functional Genomics, Novartis Institute for Biomedical Research, 100 Technology Square, Cambridge, MA 02139; and ‡Genomics Institute, Novartis Research Foundation, 10675 John Jay Hopkins Drive, Suite F117, San Diego, CA 92121 Edited by Peter K. Vogt, The Scripps Research Institute, La Jolla, CA, and approved July 30, 2003 (received for review May 8, 2003) This report describes an unbiased method for systematically de- of screening data and further experiments demonstrated that the termining gene function in mammalian cells. A total of 20,704 IL-8 promoter contained an unrecognized cAMP response predicted human full-length cDNAs were tested for induction of element (CRE)-like element that was activated by a protein, the IL-8 promoter. A number of genes, including those for cyto- termed transducer of regulated cAMP response element-binding kines, receptors, adapters, kinases, and transcription factors, were protein (CREB) TORC1, which is the founding member of a identified that induced the IL-8 promoter through known regula- conserved family of CREB coactivators. Thus, screening of tory sites. Proteins that acted through a cooperative interaction arrayed cDNAs represents an unbiased approach for identifica- between an AP-1 and an unrecognized cAMP response element tion of gene function and elucidation of pathways that regulate (CRE)-like site were also identified.
    [Show full text]
  • EZH2 Reduction Is an Essential Mechanoresponse for The
    Li et al. Cell Death and Disease (2020) 11:757 https://doi.org/10.1038/s41419-020-02963-3 Cell Death & Disease ARTICLE Open Access EZH2 reduction is an essential mechanoresponse for the maintenance of super-enhancer polarization against compressive stress in human periodontal ligament stem cells Qian Li1,XiwenSun2,YunyiTang2, Yanan Qu2, Yanheng Zhou1 and Yu Zhang2 Abstract Despite the ubiquitous mechanical cues at both spatial and temporal dimensions, cell identities and functions are largely immune to the everchanging mechanical stimuli. To understand the molecular basis of this epigenetic stability, we interrogated compressive force-elicited transcriptomic changes in mesenchymal stem cells purified from human periodontal ligament (PDLSCs), and identified H3K27me3 and E2F signatures populated within upregulated and weakly downregulated genes, respectively. Consistently, expressions of several E2F family transcription factors and EZH2, as core methyltransferase for H3K27me3, decreased in response to mechanical stress, which were attributed to force-induced redistribution of RB from nucleoplasm to lamina. Importantly, although epigenomic analysis on H3K27me3 landscape only demonstrated correlating changes at one group of mechanoresponsive genes, we observed a genome-wide destabilization of super-enhancers along with aberrant EZH2 retention. These super- enhancers were tightly bounded by H3K27me3 domain on one side and exhibited attenuating H3K27ac deposition fl 1234567890():,; 1234567890():,; 1234567890():,; 1234567890():,; and attening H3K27ac peaks along with compensated EZH2 expression after force exposure, analogous to increased H3K27ac entropy or decreased H3K27ac polarization. Interference of force-induced EZH2 reduction could drive actin filaments dependent spatial overlap between EZH2 and super-enhancers and functionally compromise the multipotency of PDLSC following mechanical stress. These findings together unveil a specific contribution of EZH2 reduction for the maintenance of super-enhancer stability and cell identity in mechanoresponse.
    [Show full text]