Note to users. If you're seeing this message, it means that your browser cannot find this page's style/presentation instructions -- or possibly that you are using a browser that does not support current Web standards. Find out more about why this message is appearing, and what you can do to make your experience of our site the best it can be.


Science 23 February 1996:
Vol. 271. no. 5252, pp. 1123 - 1125
DOI: 10.1126/science.271.5252.1123

Reports

Locus Control Region Function and Heterochromatin-Induced Position Effect Variegation

Richard Festenstein, (1) Mauro Tolaini, Paola Corbella, Clio Mamalaki, Jenny Parrington, Margaret Fox, Antigoni Miliou, Margaret Jones, Dimitris Kioussis (1)

Human CD2 locus control region (LCR) sequences are shown here to be essential for establishing an open chromatin configuration. Transgenic mice carrying an hCD2 minigene attached only to the 3' CD2 transcriptional enhancer exhibited variegated expression when the transgene integrated in the centromere. In contrast, mice carrying a transgene with additional 3' sequences showed no variegation even when the latter integrated in centromeric positions. This result suggests that LCRs operate by ensuring an open chromatin configuration and that a short region, with no enhancer activity, functions in the establishment, maintenance, or both of an open chromatin domain.

R. Festenstein, M. Tolaini, P. Corbella, C. Mamalaki, D. Kioussis, Division of Molecular Immunology, National Institute for Medical Research, The Ridgeway, Mill Hill, London NW7 1AA, UK.
J. Parrington, M. Fox, A. Miliou, Medical Research Council Human Biochemical Genetics Unit, Galton Laboratory, University College London, Wolfson House, 4 Stephenson Way, London NW1 2HE, UK.
M. Jones, Nuffield Department of Pathologgy, John Radcliffe Hospital, Oxford OX3 9DU, UK.
(1) To whom correspondence should be addressed.



THIS ARTICLE HAS BEEN CITED BY OTHER ARTICLES:
Regulation of Fas-mediated immune homeostasis by an activation-induced protein, Cyclon.
S. Saint Fleur, A. Hoshino, K. Kondo, T. Egawa, and H. Fujii (2009)
Blood 114, 1355-1365
   Abstract »    Full Text »    PDF »
Coexpression of Linked Genes in Mammalian Genomes Is Generally Disadvantageous.
B.-Y. Liao and J. Zhang (2008)
Mol. Biol. Evol. 25, 1555-1565
   Abstract »    Full Text »    PDF »
Investigation of the Properties of Non-gypsy Suppressor of Hairy-wing-Binding Sites.
E. J. Kuhn-Parnell, C. Helou, D. J. Marion, B. L. Gilmore, T. J. Parnell, M. S. Wold, and P. K. Geyer (2008)
Genetics 179, 1263-1273
   Abstract »    Full Text »    PDF »
Position effect variegation and imprinting of transgenes in lymphocytes.
A. Williams, N. Harker, E. Ktistaki, H. Veiga-Fernandes, K. Roderick, M. Tolaini, T. Norton, K. Williams, and D. Kioussis (2008)
Nucleic Acids Res. 36, 2320-2329
   Abstract »    Full Text »    PDF »
CTCF-Independent, but Not CTCF-Dependent, Elements Significantly Contribute to TCR-{alpha} Locus Control Region Activity.
J. Gomos-Klein, F. Harrow, J. Alarcon, and B. D. Ortiz (2007)
J. Immunol. 179, 1088-1095
   Abstract »    Full Text »    PDF »
The human vitamin D-binding protein gene contains locus control determinants sufficient for autonomous activation in hepatic chromatin..
T. Hiroki, Y.-H. Song, S. A. Liebhaber, and N. E. Cooke (2006)
Nucleic Acids Res. 34, 2154-2165
   Abstract »    Full Text »    PDF »
The TCR{alpha} Locus Control Region Specifies Thymic, But Not Peripheral, Patterns of TCR{alpha} Gene Expression.
F. Harrow and B. D. Ortiz (2005)
J. Immunol. 175, 6659-6667
   Abstract »    Full Text »    PDF »
Human High Mobility Group Box Transcription Factor 1 Affects Thymocyte Development and Transgene Variegation.
B. Sekkali, E. Szabat, E. Ktistaki, M. Tolaini, K. Roderick, N. Harker, A. Patel, K. Williams, T. Norton, and D. Kioussis (2005)
J. Immunol. 175, 5203-5212
   Abstract »    Full Text »    PDF »
Remote control of gene transcription.
A. G. West and P. Fraser (2005)
Hum. Mol. Genet. 14, R101-R111
   Abstract »    Full Text »    PDF »
Performance of Genomic Bordering Elements at Predefined Genomic Loci.
S. Goetze, A. Baer, S. Winkelmann, K. Nehlsen, J. Seibler, K. Maass, and J. Bode (2005)
Mol. Cell. Biol. 25, 2260-2272
   Abstract »    Full Text »    PDF »
Onset and inheritance of abnormal epigenetic regulation in hematopoietic cells.
S. Bottardi, V. Bourgoin, N. Pierre-Charles, and E. Milot (2005)
Hum. Mol. Genet. 14, 493-502
   Abstract »    Full Text »    PDF »
Activation and Tolerance in CD4+ T Cells Reactive to an Immunoglobulin Variable Region.
C. M. Snyder, K. Aviszus, R. A. Heiser, D. R. Tonkin, A. M. Guth, and L. J. Wysocki (2004)
J. Exp. Med.
   Abstract »    Full Text »    PDF »
Genomic Ly49A Transgenes: Basis of Variegated Ly49A Gene Expression and Identification of a Critical Regulatory Element.
D. M. Tanamachi, D. C. Moniot, D. Cado, S. D. Liu, J. K. Hsia, and D. H. Raulet (2004)
J. Immunol. 172, 1074-1082
   Abstract »    Full Text »    PDF »
Persistent {gamma}-globin expression in adult transgenic mice is mediated by HPFH-2, HPFH-3, and HPFH-6 breakpoint sequences.
E. Z. Katsantoni, A. Langeveld, A. W. K. Wai, D. Drabek, F. Grosveld, N. P. Anagnou, and J. Strouboulis (2003)
Blood 102, 3412-3419
   Abstract »    Full Text »    PDF »
Development of a macromolecular diffusion pathway in the lens.
V. I. Shestopalov and S. Bassnett (2003)
J. Cell Sci. 116, 4191-4199
   Abstract »    Full Text »    PDF »
STAT4 Requires the N-terminal Domain for Efficient Phosphorylation.
H.-C. Chang, S. Zhang, I. Oldham, L. Naeger, T. Hoey, and M. H. Kaplan (2003)
J. Biol. Chem. 278, 32471-32477
   Abstract »    Full Text »    PDF »
Chronic Exposure to Low Levels of Antigen in the Periphery Causes Reversible Functional Impairment Correlating with Changes in CD5 Levels in Monoclonal CD8 T Cells.
P. Stamou, J. de Jersey, D. Carmignac, C. Mamalaki, D. Kioussis, and B. Stockinger (2003)
J. Immunol. 171, 1278-1284
   Abstract »    Full Text »    PDF »
Mammalian linker-histone subtypes differentially affect gene expression invivo.
R. Alami, Y. Fan, S. Pack, T. M. Sonbuchner, A. Besse, Q. Lin, J. M. Greally, A. I. Skoultchi, and E. E. Bouhassira (2003)
PNAS 100, 5920-5925
   Abstract »    Full Text »    PDF »
Expression of a Constitutively Active Stat6 In Vivo Alters Lymphocyte Homeostasis with Distinct Effects in T and B Cells.
H. A. Bruns, U. Schindler, and M. H. Kaplan (2003)
J. Immunol. 170, 3478-3487
   Abstract »    Full Text »    PDF »
Modulation of Heterochromatin Protein 1 Dynamics in Primary Mammalian Cells.
R. Festenstein, S. N. Pagakis, K. Hiragami, D. Lyon, A. Verreault, B. Sekkali, and D. Kioussis (2003)
Science 299, 719-721
   Abstract »    Full Text »    PDF »
Sorting nexin 3 (SNX3) is disrupted in a patient with a translocation t(6;13)(q21;q12) and microcephaly, microphthalmia, ectrodactyly, prognathism (MMEP) phenotype.
V S Vervoort, D Viljoen, R Smart, G Suthers, B R DuPont, A Abbott, and C E Schwartz (2002)
J. Med. Genet. 39, 893-899
   Abstract »    Full Text »    PDF »
Locus control regions.
Q. Li, K. R. Peterson, X. Fang, and G. Stamatoyannopoulos (2002)
Blood 100, 3077-3086
   Abstract »    Full Text »    PDF »
cis Elements of the Villin Gene Control Expression in Restricted Domains of the Vertical (Crypt) and Horizontal (Duodenum, Cecum) Axes of the Intestine.
B. B. Madison, L. Dunbar, X. T. Qiao, K. Braunstein, E. Braunstein, and D. L. Gumucio (2002)
J. Biol. Chem. 277, 33275-33283
   Abstract »    Full Text »    PDF »
The T-Lineage-affiliated CD2 Gene Lies within an Open Chromatin Environment in Acute Promyelocytic Leukemia Cells.
D. Grimwade, S. V. Outram, R. Flora, S. J. Ings, A. R. Pizzey, R. Morilla, C. F. Craddock, D. C. Linch, and E. Solomon (2002)
Cancer Res. 62, 4730-4735
   Abstract »    Full Text »    PDF »
Comparison of Gene Expression During Preimplantation Development Between Diploid and Haploid Mouse Embryos.
K. E. Latham, H. Akutsu, B. Patel, and R. Yanagimachi (2002)
Biol Reprod 67, 386-392
   Abstract »    Full Text »    PDF »
Understanding adipose tissue development from transgenic animal models.
P. Valet, G. Tavernier, I. Castan-Laurell, J. S. Saulnier-Blache, and D. Langin (2002)
J. Lipid Res. 43, 835-860
   Abstract »    Full Text »    PDF »
Multiple Effects of Genetic Background on Variegated Transgene Expression in Mice.
M. L. Opsahl, M. McClenaghan, A. Springbett, S. Reid, R. Lathe, A. Colman, and C. B. A. Whitelaw (2002)
Genetics 160, 1107-1112
   Abstract »    Full Text »    PDF »
In Vivo Analysis of Retroviral Enhancer Mutations in Hematopoietic Cells: SP1/EGR1 and ETS/GATA Motifs Contribute to Long Terminal Repeat Specificity.
A. Wahlers, P. F. Zipfel, M. Schwieger, W. Ostertag, and C. Baum (2002)
J. Virol. 76, 303-312
   Abstract »    Full Text »    PDF »
Effects of CD2 locus control region sequences on gene expression by retroviral and lentiviral vectors.
S. Indraccolo, S. Minuzzo, F. Roccaforte, R. Zamarchi, W. Habeler, L. Stievano, V. Tosello, D. Klein, W. H. Gunzburg, G. Basso, et al. (2001)
Blood 98, 3607-3617
   Abstract »    Full Text »    PDF »
Enforced Expression of GATA-3 During T Cell Development Inhibits Maturation of CD8 Single-Positive Cells and Induces Thymic Lymphoma in Transgenic Mice.
M. C. Nawijn, R. Ferreira, G. M. Dingjan, O. Kahre, D. Drabek, A. Karis, F. Grosveld, and R. W. Hendriks (2001)
J. Immunol. 167, 715-723
   Abstract »    Full Text »    PDF »
The OMP-lacZ Transgene Mimics the Unusual Expression Pattern of OR-Z6, a New Odorant Receptor Gene on Mouse Chromosome 6: Implication for Locus-Dependent Gene Expression.
M. Pyrski, Z. Xu, E. Walters, D. J. Gilbert, N. A. Jenkins, N. G. Copeland, and F. L. Margolis (2001)
J. Neurosci. 21, 4637-4648
   Abstract »    Full Text »    PDF »
A NF-{{kappa}}B/Sp1 Region Is Essential for Chromatin Remodeling and Correct Transcription of a Human Granulocyte- Macrophage Colony-Stimulating Factor Transgene.
D. Cakouros, P. N. Cockerill, A. G. Bert, R. Mital, D. C. Roberts, and M. F. Shannon (2001)
J. Immunol. 167, 302-310
   Abstract »    Full Text »    PDF »
Locus Control Region of the Human CD2 Gene in a Lentivirus Vector Confers Position-Independent Transgene Expression.
C. M. Kowolik, J. Hu, and J.-K. Yee (2001)
J. Virol. 75, 4641-4648
   Abstract »    Full Text »    PDF »
Sequence and Chromosomal Context Effects on Variegated Expression of Keratin 5/lacZ Constructs in Stratified Epithelia of Transgenic Mice.
A. Ramírez, E. Milot, I. Ponsa, C. Marcos-Gutiérrez, A. Page, M. Santos, J. Jorcano, and M. Vidal (2001)
Genetics 158, 341-350
   Abstract »    Full Text »
A Role for CCAAT/Enhancer Binding Protein {beta}-Liver-enriched Inhibitory Protein in Mammary Epithelial Cell Proliferation.
C. A. Zahnow, R. D. Cardiff, R. Laucirica, D. Medina, and J. M. Rosen (2001)
Cancer Res. 61, 261-269
   Abstract »    Full Text »
Chromatin Remodeling by the T Cell Receptor (Tcr)-{beta} Gene Enhancer during Early T Cell Development: Implications for the Control of Tcr-{beta} Locus Recombination.
N. Mathieu, W. M. Hempel, S. Spicuglia, C. Verthuy, and P. Ferrier (2000)
J. Exp. Med. 192, 625-636
   Abstract »    Full Text »    PDF »
Molecular Determinants for Targeting Heterochromatin Protein 1-Mediated Gene Silencing: Direct Chromoshadow Domain-KAP-1 Corepressor Interaction Is Essential.
M. S. Lechner, G. E. Begg, D. W. Speicher, and F. J. Rauscher III (2000)
Mol. Cell. Biol. 20, 6449-6465
   Abstract »    Full Text »    PDF »
Characteristics of the Adeno-Associated Virus Preintegration Site in Human Chromosome 19: Open Chromatin Conformation and Transcription-Competent Environment.
S. Lamartina, E. Sporeno, E. Fattori, and C. Toniatti (2000)
J. Virol. 74, 7671-7677
   Abstract »    Full Text »    PDF »
alpha -Thalassemia resulting from a negative chromosomal position effect.
V. M. Barbour, C. Tufarelli, J. A. Sharpe, Z. E. Smith, H. Ayyub, C. A. Heinlein, J. Sloane-Stanley, K. Indrak, W. G. Wood, and D. R. Higgs (2000)
Blood 96, 800-807
   Abstract »    Full Text »    PDF »
The cHS4 Insulator Increases the Probability of Retroviral Expression at Random Chromosomal Integration Sites.
S. Rivella, J. A. Callegari, C. May, C. W. Tan, and M. Sadelain (2000)
J. Virol. 74, 4679-4687
   Abstract »    Full Text »    PDF »
{beta}-globin YAC transgenes exhibit uniform expression levels but position effect variegation in mice.
R. Alami, J. M. Greally, K. Tanimoto, S. Hwang, Y.-Q. Feng, J. D. Engel, S. Fiering, and E. E. Bouhassira (2000)
Hum. Mol. Genet. 9, 631-636
   Abstract »    Full Text »    PDF »
An Alu Element from the K18 Gene Confers Position-independent Expression in Transgenic Mice.
D. A. Willoughby, A. Vilalta, and R. G. Oshima (2000)
J. Biol. Chem. 275, 759-768
   Abstract »    Full Text »    PDF »
Definition of a T-Cell Receptor beta Gene Core Enhancer of V(D)J Recombination by Transgenic Mapping.
R. K. Tripathi, N. Mathieu, S. Spicuglia, D. Payet, C. Verthuy, G. Bouvier, D. Depetris, M.-G. Mattei, W. M. HempeL, and P. Ferrier (2000)
Mol. Cell. Biol. 20, 42-53
   Abstract »    Full Text »    PDF »
Duplication and Maintenance of Heterochromatin Domains.
A. Taddei, D. Roche, J.-B. Sibarita, B. M. Turner, and G. Almouzni (1999)
J. Cell Biol. 147, 1153-1166
   Abstract »    Full Text »    PDF »
Pit-1 Binding Sites at the Somatotrope-specific DNase I Hypersensitive Sites I, II of the Human Growth Hormone Locus Control Region Are Essential for in Vivo hGH-N Gene Activation.
B. M. Shewchuk, S. L. Asa, N. E. Cooke, and S. A. Liebhaber (1999)
J. Biol. Chem. 274, 35725-35733
   Abstract »    Full Text »    PDF »
Nuclear matrix attachment regions antagonize methylation-dependent repression of long-range enhancer-promoter interactions.
W. C. Forrester, L. A. Fernández, and R. Grosschedl (1999)
Genes & Dev. 13, 3003-3014
   Abstract »    Full Text »
Variegated Expression of the Endogenous Immunoglobulin Heavy-Chain Gene in the Absence of the Intronic Locus Control Region.
D. Ronai, M. Berru, and M. J. Shulman (1999)
Mol. Cell. Biol. 19, 7031-7040
   Abstract »    Full Text »    PDF »
Enhancer Blocking by the Drosophila gypsy Insulator Depends Upon Insulator Anatomy and Enhancer Strength.
K. C. Scott, A. D. Taubman, and P. K. Geyer (1999)
Genetics 153, 787-798
   Abstract »    Full Text »    PDF »
Promoter Elements of vav Drive Transgene Expression In Vivo Throughout the Hematopoietic Compartment.
S. Ogilvy, D. Metcalf, L. Gibson, M. L. Bath, A. W. Harris, and J. M. Adams (1999)
Blood 94, 1855-1863
   Abstract »    Full Text »    PDF »
A Novel Element Upstream of the V{gamma}2 Gene in the Murine T Cell Receptor {gamma} Locus Cooperates with the 3' Enhancer to Act as a Locus Control Region.
J. E. Baker, J. Kang, N. Xiong, T. Chen, D. Cado, and D. H. Raulet (1999)
J. Exp. Med. 190, 669-680
   Abstract »    Full Text »    PDF »
The Evolution of Trichromatic Color Vision by Opsin Gene Duplication in New World and Old World Primates.
K. S. Dulai, M. von Dornum, J. D. Mollon, and D. M. Hunt (1999)
Genome Res. 9, 629-638
   Abstract »    Full Text »
The Mouse GATA-2 Gene is Expressed in the Para-Aortic Splanchnopleura and Aorta-Gonads and Mesonephros Region.
N. Minegishi, J. Ohta, H. Yamagiwa, N. Suzuki, S. Kawauchi, Y. Zhou, S. Takahashi, N. Hayashi, J. D. Engel, and M. Yamamoto (1999)
Blood 93, 4196-4207
   Abstract »    Full Text »    PDF »
Pairing-Dependent Mislocalization of a Drosophila brown Gene Reporter to a Heterochromatic Environment.
G. L. Sass and S. Henikoff (1999)
Genetics 152, 595-604
   Abstract »    Full Text »
The TCR {zeta}-Chain Immunoreceptor Tyrosine-Based Activation Motifs Are Sufficient for the Activation and Differentiation of Primary T Lymphocytes.
T. L. Geiger, D. Leitenberg, and R. A. Flavell (1999)
J. Immunol. 162, 5931-5939
   Abstract »    Full Text »    PDF »
A Nonessential HP1-Like Protein Affects Starvation-Induced Assembly of Condensed Chromatin and Gene Expression in Macronuclei of Tetrahymena thermophila.
H. Huang, J. F. Smothers, E. A. Wiley, and C. D. Allis (1999)
Mol. Cell. Biol. 19, 3624-3634
   Abstract »    Full Text »    PDF »
The Chicken beta -Globin 5'HS4 Boundary Element Blocks Enhancer-Mediated Suppression of Silencing.
M. C. Walters, S. Fiering, E. E. Bouhassira, D. Scalzo, S. Goeke, W. Magis, D. Garrick, E. Whitelaw, and D. I. K. Martin (1999)
Mol. Cell. Biol. 19, 3714-3726
   Abstract »    Full Text »    PDF »
The Cre/loxP system and gene targeting in the kidney.
P. K. Stricklett, R. D. Nelson, and D. E. Kohan (1999)
Am J Physiol Renal Physiol 276, F651-F657
   Abstract »    Full Text »    PDF »
A New Element within the T-Cell Receptor alpha  Locus Required for Tissue-Specific Locus Control Region Activity.
B. D. Ortiz, D. Cado, and A. Winoto (1999)
Mol. Cell. Biol. 19, 1901-1909
   Abstract »    Full Text »    PDF »
Ig Heavy Chain Expression and Class Switching In Vitro from an Allele Lacking the 3' Enhancers DNase I-Hypersensitive hs3A and hs1,2.
S. Saleque, M. Singh, and B. K. Birshtein (1999)
J. Immunol. 162, 2791-2803
   Abstract »    Full Text »    PDF »
Analysis of Mice with Single and Multiple Copies of Transgenes Reveals a Novel Arrangement for the lambda 5-VpreB1 Locus Control Region.
P. Sabbattini, A. Georgiou, C. Sinclair, and N. Dillon (1999)
Mol. Cell. Biol. 19, 671-679
   Abstract »    Full Text »    PDF »
The Immunoglobulin Heavy Chain Locus Control Region Increases Histone Acetylation along Linked c-myc Genes.
L. Madisen, A. Krumm, T. R. Hebbes, and M. Groudine (1998)
Mol. Cell. Biol. 18, 6281-6292
   Abstract »    Full Text »    PDF »
The Locus Control Region Is Necessary for Gene Expression in the Human beta -Globin Locus but Not the Maintenance of an Open Chromatin Structure in Erythroid Cells.
A. Reik, A. Telling, G. Zitnik, D. Cimbora, E. Epner, and M. Groudine (1998)
Mol. Cell. Biol. 18, 5992-6000
   Abstract »    Full Text »    PDF »
Loss of transcriptional activity of a transgene is accompanied by DNA methylation and histone deacetylation and is prevented by insulators.
M. J. Pikaart, F. Recillas-Targa, and G. Felsenfeld (1998)
Genes & Dev. 12, 2852-2862
   Abstract »    Full Text »
Expression of an AQP2 Cre recombinase transgene in kidney and male reproductive system of transgenic mice.
R. D. Nelson, P. Stricklett, C. Gustafson, A. Stevens, D. Ausiello, D. Brown, and D. E. Kohan (1998)
Am J Physiol Cell Physiol 275, C216-C226
   Abstract »    Full Text »    PDF »
Fetal Mouse NK Cell Clones Are Deficient in Ly49 Expression, Share a Common Broad Lytic Specificity, and Undergo Continuous and Extensive Diversification In Vitro.
M. S. Manoussaka, R. J. Smith, V. Conlin, J. A. Toomey, and C. G. Brooks (1998)
J. Immunol. 160, 2197-2206
   Abstract »    Full Text »    PDF »
Transcriptional Regulation of vav, a Gene Expressed Throughout the Hematopoietic Compartment.
S. Ogilvy, A. G. Elefanty, J. Visvader, M. L. Bath, A. W. Harris, and J. M. Adams (1998)
Blood 91, 419-430
   Abstract »    Full Text »    PDF »
Nuclear Matrix Attachment Regions Confer Long-range Function upon the Immunoglobulin {micro} Enhancer.
L.A. FERNANDEZ, M. WINKLER, W. FORRESTER, T. JENUWEIN, and R. GROSSCHEDL (1998)
Cold Spring Harb Symp Quant Biol 63, 515-524
   Abstract »    PDF »
Conserved Enhancer Elements in Human and Mouse Renin Genes Have Different Transcriptional Effects in As4.1 Cells.
Y. Yan, C. A. Jones, C. D. Sigmund, K. W. Gross, and D. F. Catanzaro (1997)
Circ. Res. 81, 558-566
   Abstract »    Full Text »
Natural Killer Cell Tolerance in Mice with Mosaic Expression of Major Histocompatibility Complex Class I Transgene.
M. H. Johansson, C. Bieberich, G. Jay, K. Karre, and P. Hoglund (1997)
J. Exp. Med. 186, 353-364
   Abstract »    Full Text »    PDF »
An upstream, DNase I hypersensitive region of the hematopoietic-expressed transcription factor GATA-1 gene confers developmental specificity in transgenic mice.
M. A. McDevitt, Y. Fujiwara, R. A. Shivdasani, and S. H. Orkin (1997)
PNAS 94, 7976-7981
   Abstract »    Full Text »    PDF »
A Functional Rhodopsin-Green Fluorescent Protein Fusion Protein Localizes Correctly in Transgenic Xenopus laevis Retinal Rods and Is Expressed in a Time-dependent Pattern.
O. L. Moritz, B. M. Tam, D. S. Papermaster, and T. Nakayama (2001)
J. Biol. Chem. 276, 28242-28251
   Abstract »    Full Text »    PDF »



To Advertise     Find Products


Science. ISSN 0036-8075 (print), 1095-9203 (online)