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3. Proof of concept of peptide-linked blockmiR-induced MBNL functional rescue in myotonic dystrophy type 1 mouse model

Author

Overby S, Cerro-Herreros E, Gonzalez-Martinez I, Varela M, Seoane-Miraz D, Jad Y, Raz R, Moller T, Perez-Alonso M, Wood M, Llamusi B, and Artero R

Abstract

Myotonic dystrophy type 1 is a debilitating neuromuscular disease causing muscle weakness, myotonia, and cardiac dysfunction. The phenotypes are caused by muscleblind-like (MBNL) protein sequestration by toxic RNA in the DM1 protein kinase (DMPK) gene. DM1 patients exhibit a pathogenic number of repetitions in DMPK, which leads to downstream symptoms. Another disease characteristic is altered microRNA (miRNA) expression. It was previously shown that miR-23b regulates the translation of MBNL1 into protein. Antisense oligonucleotide (AON) treatment targeting this miRNA can improve disease symptoms. Here, we present a refinement of this strategy targeting a miR-23b binding site on the MBNL1 3MODIFIER LETTER PRIME UTR in DM1 model cells and mice by using AONs called blockmiRs. BlockmiRs linked to novel cell-penetrating peptide chemistry showed an increase in MBNL1 protein in DM1 model cells and HSALR mice. They also showed an increase in muscle strength and significant rescue of downstream splicing and histological phenotypes in mice without disturbing the endogenous levels of other miR-23b target transcripts.

Published
2022

5. Design of novel small molecule base-pair recognizers of toxic CUG RNA transcripts characteristics of DM1

Author

Ondono R, Lirio A, Elvira C, Alvarez-Marimon E, Provenzano C, Cardinali B, Perez-Alonso M, Peralvarez-Marin A, Borrell J, Falcone G, and Estrada-Tejedor R

Subjects
congenital, hereditary, and neonatal diseases and abnormalities
Abstract

Myotonic Dystrophy type 1 (DM1) is an incurable neuromuscular disorder caused by toxic DMPK transcripts that carry CUG repeat expansions in the 3' untranslated region (3'UTR). The intrinsic complexity and lack of crystallographic data makes noncoding RNA regions challenging targets to study in the field of drug discovery. In DM1, toxic transcripts tend to stall in the nuclei forming complex inclusion bodies called foci and sequester many essential alternative splicing factors such as Muscleblind-like 1 (MBNL1). Most DM1 phenotypic features stem from the reduced availability of free MBNL1 and therefore many therapeutic efforts are focused on recovering its normal activity. For that purpose, herein we present pyrido[2,3-d]pyrimidin-7-(8H)-ones, a privileged scaffold showing remarkable biological activity against many targets involved in human disorders including cancer and viral diseases. Their combination with a flexible linker meets the requirements to stabilise DM1 toxic transcripts, and therefore, enabling the release of MBNL1. Therefore, a set of novel pyrido[2,3-d]pyrimidin-7-(8H)-ones derivatives (1a-e) were obtained using click chemistry. 1a exerted over 20% MBNL1 recovery on DM1 toxic RNA activity in primary cell biology studies using patient-derived myoblasts. 1a promising anti DM1 activity may lead to subsequent generations of ligands, highlighting a new affordable treatment against DM1.

Published
2021

7. Sequence and analysis of chromosome 4 of the plant Arabidopsis thaliana

Author

Mayer, K., Sculler, C., Wambutt, R., Murphy, G., Volckaert, G., Pohl, T., Dusterhoft, A., Stiekema, W., Entian, K.-D., Terryn, N., Harris, B., Ansorge, W., Brandt, P., Grivell, L., Rieger, M., Weichselgartner, M., Simone, V. de, Obermaier, B., Mache, R., Muller, M., Kreis, M., Delseny, M., Puigdomenech, P., Watson, M., Schmidtheini, T., Reichert, B., Portatelle, D., Perez-Alonso, M., Boutry, M., Bancroft, I., Vos, P., Hoheisel, J., Zimmermann, W., Wedler, H., Ridley, P., Langham, S.-A., McCullagh, B., Bilham, L., Robben, J., Schueren, J. Van der, Grymonprez, B., Chuang, Y.-J., Vandenbussche, F., Braeken, M., Weltjens, I., Voet, M., Bastiaens, I., Aert, R., and Defoor, E.

Subjects
Arabidopsis thaliana -- Genetic aspects, Plant chromosomes -- Research, Environmental issues, Science and technology, Zoology and wildlife conservation
Abstract

It has been possible to identify the sequence of chromosome 4 of the higher plant Arabidopsis thaliana. This chromosome is ecrocentric, with a shorter arm tipped by near-homogeneous ribosomal DNA repeats reaching for 3.5 Mb to the telomere. The complete sequence of 19,360,101 bp occurs in three contigs. Of these, two represent the short and long arms while the third, smaller one is found in the centromeric heterochromatin. The centromeric heterochromatin region of the chromosome was mapped cytogenetically to an approximately 4 Mb interval.

Published
1999

9. Therapeutic Potential of AntagomiR-23b for Treating Myotonic Dystrophy

Author

Cerro-Herreros E, Gonzalez-Martinez I, Moreno-Cervera N, Overby S, Perez-Alonso M, Llamusi B, and Artero R

Subjects
musculoskeletal diseases, congenital, hereditary, and neonatal diseases and abnormalities
Abstract

Myotonic dystrophy type 1 (DM1) is a chronically debilitating, rare genetic disease that originates from an expansion of a noncoding CTG repeat in the dystrophia myotonica protein kinase (DMPK) gene. The expansion becomes pathogenic when DMPK transcripts contain 50 or more repetitions due to the sequestration of the muscleblind-like (MBNL) family of proteins. Depletion of MBNLs causes alterations in splicing patterns in transcripts that contribute to clinical symptoms such as myotonia and muscle weakness and wasting. We previously found that microRNA (miR)-23b directly regulates MBNL1 in DM1 myoblasts and mice and that antisense technology ("antagomiRs") blocking this microRNA (miRNA) boosts MBNL1 protein levels. Here, we show the therapeutic effect over time in response to administration of antagomiR-23b as a treatment in human skeletal actin long repeat (HSALR) mice. Subcutaneous administration of antagomiR-23b upregulated the expression of MBNL1 protein and rescued splicing alterations, grip strength, and myotonia in a dose-dependent manner with long-lasting effects. Additionally, the effects of the treatment on grip strength and myotonia were still slightly notable after 45days. The pharmacokinetic data obtained provide further evidence that miR-23b could be a valid therapeutic target for DM1. Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.

Published
2020

12. miR-23b and miR-218 silencing increase Muscleblind-like expression and alleviate myotonic dystrophy phenotypes in mammalian models

Author

Cerro-Herreros E, Sabater-Arcis M, Fernandez-Costa J, Moreno N, Perez-Alonso M, Llamusi B, and Artero R

Subjects
musculoskeletal diseases, congenital, hereditary, and neonatal diseases and abnormalities
Abstract

Functional depletion of the alternative splicing factors Muscleblind-like (MBNL 1 and 2) is at the basis of the neuromuscular disease myotonic dystrophy type 1 (DM1). We previously showed the efficacy of miRNA downregulation in Drosophila DM1 model. Here, we screen for miRNAs that regulate MBNL1 and MBNL2 in HeLa cells. We thus identify miR-23b and miR218, and confirm that they downregulate MBNL proteins in this cell line. Antagonists of miR23b and miR-218 miRNAs enhance MBNL protein levels and rescue pathogenic missplicing events in DM1 myoblasts. Systemic delivery of these "antagomiRs" similarly boost MBNL expression and improve DM1-like phenotypes, including splicing alterations, histopathology, and myotonia in the HSA(LR) DM1 model mice. These mammalian data provide evidence for therapeutic blocking of the miRNAs that control Muscleblind-like protein expression in myotonic dystrophy.

Published
2018

13. Progress in Arabidopsis genome sequencing and functional genomics

Author

Wambutt, R, Murphy, G, Volckaert, G, Pohl, T, Düsterhöft, A, Stiekema, W, Entian, K.-D, Terryn, N, Harris, B, Ansorge, W, Brandt, P, Grivell, L, Rieger, M, Weichselgartner, M, de Simone, V, Obermaier, B, Mache, R, Müller, M, Kreis, M, Delseny, M, Puigdomenech, P, Watson, M, Schmidtheini, T, Reichert, B, Portatelle, D, Perez-Alonso, M, Boutry, M, Bancroft, I, Vos, P, Hoheisel, J, Zimmermann, W, Wedler, H, Ridley, P, Langham, S.-A, McCullagh, B, Bilham, L, Robben, J, Van der Schueren, J, Grymonprez, B, Chuang, Y.-J, Vandenbussche, F, Braeken, M, Weltjens, I, Voet, M, Bastiaens, I, Aert, R, Defoor, E, Weitzenegger, T, Bothe, G, Ramsperger, U, Hilbert, H, Braun, M, Holzer, E, Brandt, A, Peters, S, van Staveren, M, Dirkse, W, Mooijman, P, Klein Lankhorst, R, Rose, M, Hauf, J, Kötter, P, Berneiser, S, Hempel, S, Feldpausch, M, Lamberth, S, Van den Daele, H, De Keyser, A, Buysshaert, C, Gielen, J, Villarroel, R, De Clercq, R, Van Montagu, M, Rogers, J, Cronin, A, Quail, M, Bray-Allen, S, Clark, L, Doggett, J, Hall, S, Kay, M, Lennard, N, McLay, K, Mayes, R, Pettett, A, Rajandream, M.-A, Lyne, M, Benes, V, Rechmann, S, Borkova, D, Blöcker, H, Scharfe, M, Grimm, M, Löhnert, T.-H, Dose, S, de Haan, M, Maarse, A, Schäfer, M, Müller-Auer, S, Gabel, C, Fuchs, M, Fartmann, B, Granderath, K, Dauner, D, Herzl, A, Neumann, S, Argiriou, A, Vitale, D, Liguori, R, Piravandi, E, Massenet, O, Quigley, F, Clabauld, G, Mündlein, A, Felber, R, Schnabl, S, Hiller, R, Schmidt, W, Lecharny, A, Aubourg, S, Gy, I, Cooke, R, Berger, C, Monfort, A, Casacuberta, E, Gibbons, T, Weber, N, Vandenbol, M, Bargues, M, Terol, J, Torres, A, Perez-Perez, A, Purnelle, B, Bent, E, Johnson, S, Tacon, D, Jesse, T, Heijnen, L, Schwarz, S, Scholler, P, Heber, S, Bielke, C, Frishmann, D, Haase, D, Lemcke, K, Mewes, H.W, Stocker, S, Zaccaria, P, Mayer, K, Schüller, C, and Bevan, M

Published
2000
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14. Myotonic dystrophy: candidate small molecule therapeutics

Author

Konieczny P, Selma-Soriano E, Rapisarda AS, Fernandez-Costa JM, Perez-Alonso M, and Artero R

Subjects
musculoskeletal diseases, congenital, hereditary, and neonatal diseases and abnormalities
Abstract

Myotonic dystrophy type 1 (DM1) is a rare multisystemic neuromuscular disorder caused by expansion of CTG trinucleotide repeats in the noncoding region of the DMPK gene. Mutant DMPK transcripts are toxic and alter gene expression at several levels. Chiefly, the secondary structure formed by CUGs has a strong propensity to capture and retain proteins, like those of the muscleblind-like (MBNL) family. Sequestered MBNL proteins cannot then fulfill their normal functions. Many therapeutic approaches have been explored to reverse these pathological consequences. Here, we review the myriad of small molecules that have been proposed for DM1, including examples obtained from computational rational design, HTS, drug repurposing and therapeutic gene modulation.

Published
2017

16. Expanded CTG repeats trigger miRNA alterations in Drosophila that are conserved in myotonic dystrophy type 1 patients

Author

Fernandez-Costa JM, Garcia-Lopez A, Zuñiga S, Fernandez-Pedrosa V, Felipo-Benavent A, Mata M, Jaka O, Aiastui A, Hernandez-Torres F, Aguado B, Perez-Alonso M, Vilchez JJ, Lopez de Munain A, and Artero RD

Subjects
musculoskeletal diseases, congenital, hereditary, and neonatal diseases and abnormalities
Abstract

Myotonic dystrophy type 1 (DM1) is caused by the expansion of CTG repeats in the 3' untranslated region of the DMPK gene. Several missplicing events and transcriptional alterations have been described in DM1 patients. A large number of these defects have been reproduced in animal models expressing CTG repeats alone. Recent studies have also reported miRNA dysregulation in DM1 patients. In this work, a Drosophila model was used to investigate miRNA transcriptome alterations in the muscle, specifically triggered by CTG expansions. Twenty miRNAs were differentially expressed in CTG-expressing flies. Of these, 19 were down-regulated, whereas 1 was up-regulated. This trend was confirmed for those miRNAs conserved between Drosophila and humans (miR-1, miR-7 and miR-10) in muscle biopsies from DM1 patients. Consistently, at least seven target transcripts of these miRNAs were up-regulated in DM1 skeletal muscles. The mechanisms involved in dysregulation of miR-7 included a reduction of its primary precursor both in CTG-expressing flies and in DM1 patients. Additionally, a regulatory role for Muscleblind (Mbl) was also suggested for miR-1 and miR-7, as these miRNAs were down-regulated in flies where Mbl had been silenced. Finally, the physiological relevance of miRNA dysregulation was demonstrated for miR-10, since over-expression of this miRNA in Drosophila extended the lifespan of CTG-expressing flies. Taken together, our results contribute to our understanding of the origin and the role of miRNA alterations in DM1.

Published
2013

17. A FRET-based assay for characterization of alternative splicing events using peptide nucleic acid fluorescence in situ hybridization

Author

Blanco AM, Rausell L, Aguado B, Perez-Alonso M, and Artero R

Abstract

We describe a quantitative method for detecting RNA alternative splicing variants that combines in situ hybridization of fluorescently labeled peptide nucleic acid (PNA) probes with confocal microscopy Förster resonance energy transfer (FRET). The use of PNA probes complementary to sequences flanking a given splice junction allows to specifically quantify, within the cell, the RNA isoform generating such splice junction by FRET measure. As a proof of concept we analyzed two alternative splicing events originating from lymphocyte antigen 6 (LY6) complex, locus G5B (LY6G5B) pre-mRNA. These are characterized by the removal of the first intron (Fully Spliced Isoform, FSI) or by retention of such intron (Intron-Retained Isoform, IRI). The use of PNA probe pairs labeled with donor (Cy3) and acceptor (Cy5) fluorophores, suitable to FRET, flanking FSI and IRI specific splice junctions specifically detected both mRNA isoforms in HeLa cells. We have observed that the method works efficiently with probes 5-11 nt apart. The data supports that this FRET-based PNA fluorescence in situ hybridization (FP-FISH) method offers a conceptually new approach for characterizing at the subcellular level not only splice variant isoform structure, location and dynamics but also potentially a wide variety of close range RNA-RNA interactions.

Published
2009

18. A Snapshot of the Emerging Tomato Genome Sequence

Author

Mueller, LUKAS A., RENÉ KLEIN LANKHORST, Tanksley, STEVEN D., Giovannoni, JAMES J., Ruth, White, Julia, Vrebalov, Zhangjun, Fei, JOYCE VAN ECK, Robert, Buels, Mills, ADRI A., Naama, Menda, Tecle, ISAAK Y., Aureliano, Bombarely, Stephen, Stack, Royer, SUZANNE M., SONG BIN CHANG, Shearer, LINDSAY A., BYUNG DONG KIM, SUNG HWAN JO, CHEOL GOO HUR, Doil, Choi, CHANG BAO LI, Jiuhai, Zhao, Hongling, Jiang, Geng, Yu, Yuanyuan, Dai, Huajie, Fan, Jinfeng, Chen, Fei, Lu, Jinfeng, Shi, Shouhong, Sun, Jianjun, Chen, Xiaohua, Yang, Chen, Lu, Mingsheng, Chen, Zhukuan, Cheng, Chuanyou, Li, Hongqing, Ling, Yongbiao, Xue, Ying, Wang, Seymour, GRAHAM B., Bishop, GERARD J., Glenn, Bryan, Jane, Rogers, Sarah, Sims, Sarah, Butcher, Daniel, Buchan, James, Abbott, Helen, Beasley, Christine, Nicholson, Clare, Riddle, Sean, Humphray, Karen, Mclaren, Saloni, Mathur, Shailendra, Vyas, Solanke, AMOLKUMAR U., Rahul, Kumar, Vikrant, Gupta, Sharma, ARUN K., Paramjit, Khurana, Khurana, JITENDRA P., Akhilesh, Tyagi, Sarita, Parul, Chowdhury, Smriti, Shridhar, Debasis, Chattopadhyay, Awadhesh, Pandit, Pradeep, Singh, Ajay, Kumar, Rekha, Dixit, Archana, Singh, Sumera, Praveen, Vivek, Dalal, Mahavir, Yadav, IRFAN AHMAD GHAZI, Kishor, Gaikwad, TILAK RAJ SHARMA, Trilochan, Mohapatra, NAGENDRA KUMAR SINGH, Dóra, Szinay, HANS DE JONG, Sander, Peters, MARJO VAN STAVEREN, Erwin, Datema, Fiers, MARK W. E. J., VAN HAM, ROELAND C. H. J., Lindhout, P., Murielle, Philippot, Pierre, Frasse, Farid, Regad, Mohamed, Zouine, Mondher, Bouzayen, Erika, Asamizu, Shusei, Sato, Hiroyuki, Fukuoka, Satoshi, Tabata, Daisuke, Shibata, Botella, MIGUEL A., PEREZ ALONSO, M., FERNANDEZ PEDROSA, V., Sonia, Osorio, Amparo, Mico, Antonio, Granell, Zhonghua, Zhang, Jun, He, Sanwen, Huang, Yongchen, Du, Dongyu, Qu, Longfei, Liu, Dongyuan, Liu, Jun, Wang, Zhibiao, Ye, Wencai, Yang, Guoping, Wang, Vezzi, Alessandro, Sara, Todesco, Valle, Giorgio, Giulia, Falcone, Marco, Pietrella, Giovanni, Giuliano, Silvana, Grandillo, Alessandra, Traini, Nunzio, D'Agostino, MARIA LUISA CHIUSANO, Mara, Ercolano, Amalia, Barone, Luigi, Frusciante, Heiko, Schoof, Anika, Jöcker, Rémy, Bruggmann, Manuel, Spannagl, Mayer, KLAUS X. F., Roderic, Guigó, Francisco, Camara, Stephane, Rombauts, Fawcett, JEFFREY A., YVES VAN DE PEER, Sandra, Knapp, and DANI ZAMIR AND WILLEM STIEKEMA

Published
2009

25. Progress in Arabidopsis genome sequencing and functional genomics

Author

UCL - SST/ISV - Institut des sciences de la vie, Wambutt, R, Murphy, G, Volckaert, G, Pohl, T, Düsterhöft, A, Stiekema, W, Entian, K.-D, Terryn, N, Harris, B, Ansorge, W, Brandt, P, Grivell, L, Rieger, M, Weichselgartner, M, de Simone, V, Obermaier, B, Mache, R, Müller, M, Kreis, M, Delseny, M, Puigdomenech, P, Watson, M, Schmidtheini, T, Reichert, B, Portatelle, D, Perez-Alonso, M, Boutry, Marc, Bancroft, I, Vos, P, Hoheisel, J, Zimmermann, W, Wedler, H, Ridley, P, Langham, S.-A, McCullagh, B, Bilham, L, Robben, J, Van der Schueren, J, Grymonprez, B, Chuang, Y.-J, Vandenbussche, F, Braeken, M, Weltjens, I, Voet, M, Bastiaens, I, Aert, R, Defoor, E, Weitzenegger, T, Bothe, G, Ramsperger, U, Hilbert, H, Braun, M, Holzer, E, Brandt, A, Peters, S, van Staveren, M, Dirkse, W, Mooijman, P, Klein Lankhorst, R, Rose, M, Hauf, J, Kötter, P, Berneiser, S, Hempel, S, Feldpausch, M, Lamberth, S, Van den Daele, H, De Keyser, A, Buysshaert, C, Gielen, J, Villarroel, R, De Clercq, R, Van Montagu, M, Rogers, J, Cronin, A, Quail, M, Bray-Allen, S, Clark, L, Doggett, J, Hall, S, Kay, M, Lennard, N, McLay, K, Mayes, R, Pettett, A, Rajandream, M.-A, Lyne, M, Benes, V, Rechmann, S, Borkova, D, Blöcker, H, Scharfe, M, Grimm, M, Löhnert, T.-H, Dose, S, de Haan, M, Maarse, A, Schäfer, M, Müller-Auer, S, Gabel, C, Fuchs, M, Fartmann, B, Granderath, K, Dauner, D, Herzl, A, Neumann, S, Argiriou, A, Vitale, D, Liguori, R, Piravandi, E, Massenet, O, Quigley, F, Clabauld, G, Mündlein, A, Felber, R, Schnabl, S, Hiller, R, Schmidt, W, Lecharny, A, Aubourg, S, Gy, I, Cooke, R, Berger, C, Monfort, A, Casacuberta, E, Gibbons, T, Weber, N, Vandenbol, M, Bargues, M, Terol, J, Torres, A, Perez-Perez, A, Purnelle, B, Bent, E, Johnson, S, Tacon, D, Jesse, T, Heijnen, L, Schwarz, S, Scholler, P, Heber, S, Bielke, C, Frishmann, D, Haase, D, Lemcke, K, Mewes, H.W, Stocker, S, Zaccaria, P, Mayer, K, Schüller, C, Bevan, M, UCL - SST/ISV - Institut des sciences de la vie, Wambutt, R, Murphy, G, Volckaert, G, Pohl, T, Düsterhöft, A, Stiekema, W, Entian, K.-D, Terryn, N, Harris, B, Ansorge, W, Brandt, P, Grivell, L, Rieger, M, Weichselgartner, M, de Simone, V, Obermaier, B, Mache, R, Müller, M, Kreis, M, Delseny, M, Puigdomenech, P, Watson, M, Schmidtheini, T, Reichert, B, Portatelle, D, Perez-Alonso, M, Boutry, Marc, Bancroft, I, Vos, P, Hoheisel, J, Zimmermann, W, Wedler, H, Ridley, P, Langham, S.-A, McCullagh, B, Bilham, L, Robben, J, Van der Schueren, J, Grymonprez, B, Chuang, Y.-J, Vandenbussche, F, Braeken, M, Weltjens, I, Voet, M, Bastiaens, I, Aert, R, Defoor, E, Weitzenegger, T, Bothe, G, Ramsperger, U, Hilbert, H, Braun, M, Holzer, E, Brandt, A, Peters, S, van Staveren, M, Dirkse, W, Mooijman, P, Klein Lankhorst, R, Rose, M, Hauf, J, Kötter, P, Berneiser, S, Hempel, S, Feldpausch, M, Lamberth, S, Van den Daele, H, De Keyser, A, Buysshaert, C, Gielen, J, Villarroel, R, De Clercq, R, Van Montagu, M, Rogers, J, Cronin, A, Quail, M, Bray-Allen, S, Clark, L, Doggett, J, Hall, S, Kay, M, Lennard, N, McLay, K, Mayes, R, Pettett, A, Rajandream, M.-A, Lyne, M, Benes, V, Rechmann, S, Borkova, D, Blöcker, H, Scharfe, M, Grimm, M, Löhnert, T.-H, Dose, S, de Haan, M, Maarse, A, Schäfer, M, Müller-Auer, S, Gabel, C, Fuchs, M, Fartmann, B, Granderath, K, Dauner, D, Herzl, A, Neumann, S, Argiriou, A, Vitale, D, Liguori, R, Piravandi, E, Massenet, O, Quigley, F, Clabauld, G, Mündlein, A, Felber, R, Schnabl, S, Hiller, R, Schmidt, W, Lecharny, A, Aubourg, S, Gy, I, Cooke, R, Berger, C, Monfort, A, Casacuberta, E, Gibbons, T, Weber, N, Vandenbol, M, Bargues, M, Terol, J, Torres, A, Perez-Perez, A, Purnelle, B, Bent, E, Johnson, S, Tacon, D, Jesse, T, Heijnen, L, Schwarz, S, Scholler, P, Heber, S, Bielke, C, Frishmann, D, Haase, D, Lemcke, K, Mewes, H.W, Stocker, S, Zaccaria, P, Mayer, K, Schüller, C, and Bevan, M

Published
2000

27. Sequence and analysis of chromosome 4 of the plant Arabidopsis thaliana

Author

UCL - SST/ISV - Institut des sciences de la vie, Mayer, K., Schüller, C., Wambutt, R., Murphy, G., Volckaert, G., Pohl, T., Düsterhöft, A., Stiekema, W., Entian, K.-D., Terryn, N., Harris, B., Ansorge, W., Brandt, P., Grivell, L., Rieger, M., Weichselgartner, M., de Simone, V., Obermaier, B., Mache, R., Müller, M., Kreis, M., Delseny, M., Puigdomenech, P., Watson, M., Schmidtheini, T., Reichert, B., Portatelle, D., Perez-Alonso, M., Boutry, Marc, Bancroft, I., Vos, P., Hoheisel, J., Zimmermann, W., Wedler, H., Ridley, P., Langham, S.-A., McCullagh, B., Bilham, L., Robben, J., Van der Schueren, J., Grymonprez, B., Chuang, Y.-J., Vandenbussche, F., Braeken, M., Weltjens, I., Voet, M., Bastiaens, I., Aert, R., Defoor, E., Weitzenegger, T., Bothe, G., Ramsperger, U., Hilbert, H., Braun, M., Holzer, E., Brandt, A., Peters, S., van Staveren, M., Dirkse, W., Mooijman, P., Lankhorst, R. Klein, Rose, M., Hauf, J., Kötter, P., Berneiser, S., Hempel, S., Feldpausch, M., Lamberth, S., Van den Daele, H., De Keyser, A., Buysshaert, C., Gielen, J., Villarroel, R., De Clercq, R., Van Montagu, M., Rogers, J., Cronin, A., Quail, M., Bray-Allen, S., Clark, L., Doggett, J., Hall, S., Kay, M., Lennard, N., McLay, K., Mayes, R., Pettett, A., Rajandream, M.-A., Lyne, M., Benes, V., Rechmann, S., Borkova, D., Blöcker, H., Scharfe, M., Grimm, M., Löhnert, T.-H., Dose, S., de Haan, M., Maarse, A., Schäfer, M., Müller-Auer, S., Gabel, C., Fuchs, M., Fartmann, B., Granderath, K., Dauner, D., Herzl, A., Neumann, S., Argiriou, A., Vitale, D., Liguori, R., Piravandi, E., Massenet, O., Quigley, F., Clabauld, G., Mündlein, A., Felber, R., Schnabl, S., Hiller, R., Schmidt, W., Lecharny, A., Aubourg, S., Chefdor, F., Cooke, R., Berger, C., Montfort, A., Casacuberta, E., Gibbons, T., Weber, N., Vandenbol, M., Bargues, M., Terol, J., Torres, A., Perez-Perez, A., Purnelle, B., Bent, E., Johnson, S., Tacon, D., Jesse, T., Heijnen, L., Schwarz, S., Scholler, P., Heber, S., Francs, P., Bielke, C., Frishman, D., Haase, D., Lemcke, K., Mewes, H. W., Stocker, S., Zaccaria, P., Wilson, R. K., de la Bastide, M., Habermann, K., Parnell, L., Dedhia, N., Gnoj, L., Schutz, K., Huang, E., Spiegel, L., Sehkon, M., Murray, J., Sheet, P., Cordes, M., Abu-Threideh, J., Stoneking, T., Kalicki, J., Graves, T., Harmon, G., Edwards, J., Latreille, P., Courtney, L., Cloud, J., Abbott, A., Scott, K., Johnson, D., Minx, P., Bentley, D., Fulton, B., Miller, N., Greco, T., Kemp, K., Kramer, J., Fulton, L., Mardis, E., Dante, M., Pepin, K., Hillier, L., Nelson, J., Spieth, J., Ryan, E., Andrews, S., Geisel, C., Layman, D., Du, H., Ali, J., Berghoff, A., Jones, K., Drone, K., Cotton, M., Joshu, C., Antonoiu, B., Zidanic, M., Strong, C., Sun, H., Lamar, B., Yordan, C., Ma, P., Zhong, J., Preston, R., Vil, D., Shekher, M., Matero, A., Shah, R., Swaby, I'K., O'Shaughnessy, A., Rodriguez, M., Hoffman, J., Till, S., Granat, S., Shohdy, N., Hasegawa, A., Hameed, A., Lodhi, M., Johnson, A., Chen, E., Marra, M., Martienssen, R., McCombie, W. R., UCL - SST/ISV - Institut des sciences de la vie, Mayer, K., Schüller, C., Wambutt, R., Murphy, G., Volckaert, G., Pohl, T., Düsterhöft, A., Stiekema, W., Entian, K.-D., Terryn, N., Harris, B., Ansorge, W., Brandt, P., Grivell, L., Rieger, M., Weichselgartner, M., de Simone, V., Obermaier, B., Mache, R., Müller, M., Kreis, M., Delseny, M., Puigdomenech, P., Watson, M., Schmidtheini, T., Reichert, B., Portatelle, D., Perez-Alonso, M., Boutry, Marc, Bancroft, I., Vos, P., Hoheisel, J., Zimmermann, W., Wedler, H., Ridley, P., Langham, S.-A., McCullagh, B., Bilham, L., Robben, J., Van der Schueren, J., Grymonprez, B., Chuang, Y.-J., Vandenbussche, F., Braeken, M., Weltjens, I., Voet, M., Bastiaens, I., Aert, R., Defoor, E., Weitzenegger, T., Bothe, G., Ramsperger, U., Hilbert, H., Braun, M., Holzer, E., Brandt, A., Peters, S., van Staveren, M., Dirkse, W., Mooijman, P., Lankhorst, R. Klein, Rose, M., Hauf, J., Kötter, P., Berneiser, S., Hempel, S., Feldpausch, M., Lamberth, S., Van den Daele, H., De Keyser, A., Buysshaert, C., Gielen, J., Villarroel, R., De Clercq, R., Van Montagu, M., Rogers, J., Cronin, A., Quail, M., Bray-Allen, S., Clark, L., Doggett, J., Hall, S., Kay, M., Lennard, N., McLay, K., Mayes, R., Pettett, A., Rajandream, M.-A., Lyne, M., Benes, V., Rechmann, S., Borkova, D., Blöcker, H., Scharfe, M., Grimm, M., Löhnert, T.-H., Dose, S., de Haan, M., Maarse, A., Schäfer, M., Müller-Auer, S., Gabel, C., Fuchs, M., Fartmann, B., Granderath, K., Dauner, D., Herzl, A., Neumann, S., Argiriou, A., Vitale, D., Liguori, R., Piravandi, E., Massenet, O., Quigley, F., Clabauld, G., Mündlein, A., Felber, R., Schnabl, S., Hiller, R., Schmidt, W., Lecharny, A., Aubourg, S., Chefdor, F., Cooke, R., Berger, C., Montfort, A., Casacuberta, E., Gibbons, T., Weber, N., Vandenbol, M., Bargues, M., Terol, J., Torres, A., Perez-Perez, A., Purnelle, B., Bent, E., Johnson, S., Tacon, D., Jesse, T., Heijnen, L., Schwarz, S., Scholler, P., Heber, S., Francs, P., Bielke, C., Frishman, D., Haase, D., Lemcke, K., Mewes, H. W., Stocker, S., Zaccaria, P., Wilson, R. K., de la Bastide, M., Habermann, K., Parnell, L., Dedhia, N., Gnoj, L., Schutz, K., Huang, E., Spiegel, L., Sehkon, M., Murray, J., Sheet, P., Cordes, M., Abu-Threideh, J., Stoneking, T., Kalicki, J., Graves, T., Harmon, G., Edwards, J., Latreille, P., Courtney, L., Cloud, J., Abbott, A., Scott, K., Johnson, D., Minx, P., Bentley, D., Fulton, B., Miller, N., Greco, T., Kemp, K., Kramer, J., Fulton, L., Mardis, E., Dante, M., Pepin, K., Hillier, L., Nelson, J., Spieth, J., Ryan, E., Andrews, S., Geisel, C., Layman, D., Du, H., Ali, J., Berghoff, A., Jones, K., Drone, K., Cotton, M., Joshu, C., Antonoiu, B., Zidanic, M., Strong, C., Sun, H., Lamar, B., Yordan, C., Ma, P., Zhong, J., Preston, R., Vil, D., Shekher, M., Matero, A., Shah, R., Swaby, I'K., O'Shaughnessy, A., Rodriguez, M., Hoffman, J., Till, S., Granat, S., Shohdy, N., Hasegawa, A., Hameed, A., Lodhi, M., Johnson, A., Chen, E., Marra, M., Martienssen, R., and McCombie, W. R.

Abstract

The higher plant Arabidopsis thaliana (Arabidopsis) is an important model for identifying plant genes and determining their function. To assist biological investigations and to define chromosome structure, a coordinated effort to sequence the Arabidopsis genome was initiated in late 1996. Here we report one of the first milestones of this project, the sequence of chromosome 4. Analysis of 17.38 megabases of unique sequence, representing about 17% of the genome, reveals 3,744 protein coding genes, 81 transfer RNAs and numerous repeat elements. Heterochromatic regions surrounding the putative centromere, which has not yet been completely sequenced, are characterized by an increased frequency of a variety of repeats, new repeats, reduced recombination, lowered gene density and lowered gene expression. Roughly 60% of the predicted protein-coding genes have been functionally characterized on the basis of their homology to known genes. Many genes encode predicted proteins that are homologous to human and Caenorhabditis elegans proteins.

Published
1999

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