This Article
Right arrow Full Text
Right arrow Full Text (PDF)
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrowReprints and Permissions
Right arrow Copyright Information
Right arrow Books from ASM Press
Right arrow MicrobeWorld
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Reik, A.
Right arrow Articles by Groudine, M.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Reik, A.
Right arrow Articles by Groudine, M.

 Previous Article  |  Next Article 

Molecular and Cellular Biology, October 1998, p. 5992-6000, Vol. 18, No. 10
0270-7306/98/$04.00+0
Copyright © 1998, American Society for Microbiology. All rights reserved.

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

Andreas Reik,1 Agnes Telling,1 Galynn Zitnik,1 Daniel Cimbora,1 Elliot Epner,1,dagger and Mark Groudine1,2,*

Division of Basic Science, Fred Hutchinson Cancer Research Center, Seattle, Washington 98109,1 and Department of Radiation Oncology, University of Washington Medical School, Seattle, Washington 981952

Received 19 May 1998/Accepted 30 June 1998

Studies in many systems have led to the model that the human beta -globin locus control region (LCR) regulates the transcription, chromatin structure, and replication properties of the beta -globin locus. However the precise mechanisms of this regulation are unknown. We have developed strategies to use homologous recombination in a tissue culture system to examine how the LCR regulates the locus in its natural chromosomal environment. Our results show that when the functional components of the LCR, as defined by transfection and transgenic studies, are deleted from the endogenous beta -globin locus in an erythroid background, transcription of all beta -globin genes is abolished in every cell. However, formation of the remaining hypersensitive site(s) of the LCR and the presence of a DNase I-sensitive structure of the beta -globin locus are not affected by the deletion. In contrast, deletion of 5'HS5 of the LCR, which has been suggested to serve as an insulator, has only a minor effect on beta -globin transcription and does not influence the chromatin structure of the locus. These results show that the LCR as currently defined is not necessary to keep the locus in an "open" conformation in erythroid cells and that even in an erythroid environment an open locus is not sufficient to permit transcription of the beta -like globin genes.

* Corresponding author. Mailing address: Division of Basic Science, Fred Hutchinson Cancer Research Center, 1100 Fairview Ave. N., Seattle, WA 98109. Phone: (206) 667-4497. Fax: (206) 667-5894. E-mail: markg{at}fhcrc.org.

dagger Present address: Department of Medicine, Arizona Cancer Center, University of Arizona, Tucson, AZ 85724.

Molecular and Cellular Biology, October 1998, p. 5992-6000, Vol. 18, No. 10
0270-7306/98/$04.00+0
Copyright © 1998, American Society for Microbiology. All rights reserved.


This article has been cited by other articles:

  • Beauchemin, H., Trudel, M. (2009). Evidence for a Bigenic Chromatin Subdomain in Regulation of the Fetal-to-Adult Hemoglobin Switch. Mol. Cell. Biol. 29: 1635-1648 [Abstract] [Full Text]  
  • Zhu, X., Ling, J., Zhang, L., Pi, W., Wu, M., Tuan, D. (2007). A facilitated tracking and transcription mechanism of long-range enhancer function. Nucleic Acids Res 0: gkm595v1-13 [Abstract] [Full Text]  
  • Prasanth, K. V., Spector, D. L. (2007). Eukaryotic regulatory RNAs: an answer to the 'genome complexity' conundrum. Genes Dev. 21: 11-42 [Abstract] [Full Text]  
  • Bender, M. A., Byron, R., Ragoczy, T., Telling, A., Bulger, M., Groudine, M. (2006). Flanking HS-62.5 and 3' HS1, and regions upstream of the LCR, are not required for beta-globin transcription. Blood 108: 1395-1401 [Abstract] [Full Text]  
  • Brown, J. M., Leach, J., Reittie, J. E., Atzberger, A., Lee-Prudhoe, J., Wood, W. G., Higgs, D. R., Iborra, F. J., Buckle, V. J. (2006). Coregulated human globin genes are frequently in spatial proximity when active. JCB 172: 177-187 [Abstract] [Full Text]  
  • Haussecker, D., Proudfoot, N. J. (2005). Dicer-Dependent Turnover of Intergenic Transcripts from the Human {beta}-Globin Gene Cluster. Mol. Cell. Biol. 25: 9724-9733 [Abstract] [Full Text]  
  • Yu, X., Zhu, X., Pi, W., Ling, J., Ko, L., Takeda, Y., Tuan, D. (2005). The Long Terminal Repeat (LTR) of ERV-9 Human Endogenous Retrovirus Binds to NF-Y in the Assembly of an Active LTR Enhancer Complex NF-Y/MZF1/GATA-2. J. Biol. Chem. 280: 35184-35194 [Abstract] [Full Text]  
  • Mahajan, M. C., Narlikar, G. J., Boyapaty, G., Kingston, R. E., Weissman, S. M. (2005). Heterogeneous nuclear ribonucleoprotein C1/C2, MeCP1, and SWI/SNF form a chromatin remodeling complex at the {beta}-globin locus control region. Proc. Natl. Acad. Sci. USA 102: 15012-15017 [Abstract] [Full Text]  
  • Fang, X., Sun, J., Xiang, P., Yu, M., Navas, P. A., Peterson, K. R., Stamatoyannopoulos, G., Li, Q. (2005). Synergistic and Additive Properties of the Beta-Globin Locus Control Region (LCR) Revealed by 5'HS3 Deletion Mutations: Implication for LCR Chromatin Architecture. Mol. Cell. Biol. 25: 7033-7041 [Abstract] [Full Text]  
  • Wang, J., Liu, H., Lin, C. M., Aladjem, M. I., Epner, E. M. (2005). Targeted Deletion of the Chicken {beta}-Globin Regulatory Elements Reveals a Cooperative Gene Silencing Activity. J. Biol. Chem. 280: 23340-23348 [Abstract] [Full Text]  
  • West, A. G., Fraser, P. (2005). Remote control of gene transcription. Hum Mol Genet 14: R101-R111 [Abstract] [Full Text]  
  • Bottardi, S., Bourgoin, V., Pierre-Charles, N., Milot, E. (2005). Onset and inheritance of abnormal epigenetic regulation in hematopoietic cells. Hum Mol Genet 14: 493-502 [Abstract] [Full Text]  
  • Harrow, F., Amuta, J. U., Hutchinson, S. R., Akwaa, F., Ortiz, B. D. (2004). Factors Binding a Non-classical Cis-element Prevent Heterochromatin Effects on Locus Control Region Activity. J. Biol. Chem. 279: 17842-17849 [Abstract] [Full Text]  
  • Jin, Y., Norquay, L. D., Yang, X., Gregoire, S., Cattini, P. A. (2004). Binding of AP-2 and ETS-Domain Family Members Is Associated with Enhancer Activity in the Hypersensitive Site III Region of the Human Growth Hormone/Chorionic Somatomammotropin Locus. Mol. Endocrinol. 18: 574-587 [Abstract] [Full Text]  
  • Bottardi, S., Aumont, A., Grosveld, F., Milot, E. (2003). Developmental stage-specific epigenetic control of human {beta}-globin gene expression is potentiated in hematopoietic progenitor cells prior to their transcriptional activation. Blood 102: 3989-3997 [Abstract] [Full Text]  
  • Giraldo, P., Martinez, A., Regales, L., Lavado, A., Garcia-Diaz, A., Alonso, A., Busturia, A., Montoliu, L. (2003). Functional dissection of the mouse tyrosinase locus control region identifies a new putative boundary activity. Nucleic Acids Res 31: 6290-6305 [Abstract] [Full Text]  
  • Myers, F. A., Chong, W., Evans, D. R., Thorne, A. W., Crane-Robinson, C. (2003). Acetylation of Histone H2B Mirrors that of H4 and H3 at the Chicken {beta}-Globin Locus but Not at Housekeeping Genes. J. Biol. Chem. 278: 36315-36322 [Abstract] [Full Text]  
  • Bulger, M., Schubeler, D., Bender, M. A., Hamilton, J., Farrell, C. M., Hardison, R. C., Groudine, M. (2003). A Complex Chromatin Landscape Revealed by Patterns of Nuclease Sensitivity and Histone Modification within the Mouse {beta}-Globin Locus. Mol. Cell. Biol. 23: 5234-5244 [Abstract] [Full Text]  
  • Kang, S.-H. L., Mione Kiefer, C., Yang, T. P. (2003). Role of the Promoter in Maintaining Transcriptionally Active Chromatin Structure and DNA Methylation Patterns In Vivo. Mol. Cell. Biol. 23: 4150-4161 [Abstract] [Full Text]  
  • Ostermeier, G. C., Liu, Z., Martins, R. P., Bharadwaj, R. R., Ellis, J., Draghici, S., Krawetz, S. A. (2003). Nuclear matrix association of the human {beta}-globin locus utilizing a novel approach to quantitative real-time PCR. Nucleic Acids Res 31: 3257-3266 [Abstract] [Full Text]  
  • Gui, C.-y., Dean, A. (2003). A major role for the TATA box in recruitment of chromatin modifying complexes to a globin gene promoter. Proc. Natl. Acad. Sci. USA 100: 7009-7014 [Abstract] [Full Text]  
  • Marsden, M. D., Fournier, R. E. K. (2003). Chromosomal Elements Regulate Gene Activity and Chromatin Structure of the Human Serpin Gene Cluster at 14q32.1. Mol. Cell. Biol. 23: 3516-3526 [Abstract] [Full Text]  
  • Onishi, Y., Kiyama, R. (2003). Interaction of NF-E2 in the Human beta -Globin Locus Control Region before Chromatin Remodeling. J. Biol. Chem. 278: 8163-8171 [Abstract] [Full Text]  
  • Letting, D. L., Rakowski, C., Weiss, M. J., Blobel, G. A. (2003). Formation of a Tissue-Specific Histone Acetylation Pattern by the Hematopoietic Transcription Factor GATA-1. Mol. Cell. Biol. 23: 1334-1340 [Abstract] [Full Text]  
  • Jackson, D. A., McDowell, J. C., Dean, A. (2003). {beta}-Globin locus control region HS2 and HS3 interact structurally and functionally. Nucleic Acids Res 31: 1180-1190 [Abstract] [Full Text]  
  • Leach, K. M., Vieira, K. F., Kang, S.-H. L., Aslanian, A., Teichmann, M., Roeder, R. G., Bungert, J. (2003). Characterization of the human {beta}-globin downstream promoter region. Nucleic Acids Res 31: 1292-1301 [Abstract] [Full Text]  
  • Hu, X., Bulger, M., Roach, J. N., Eszterhas, S. K., Olivier, E., Bouhassira, E. E., Groudine, M. T., Fiering, S. (2003). Promoters of the murine embryonic beta -like globin genes Ey and beta h1 do not compete for interaction with the beta -globin locus control region. Proc. Natl. Acad. Sci. USA 100: 1111-1115 [Abstract] [Full Text]  
  • Anguita, E., Sharpe, J. A., Sloane-Stanley, J. A., Tufarelli, C., Higgs, D. R., Wood, W. G. (2002). Deletion of the mouse alpha -globin regulatory element (HS -26) has an unexpectedly mild phenotype. Blood 100: 3450-3456 [Abstract] [Full Text]  
  • Li, Q., Peterson, K. R., Fang, X., Stamatoyannopoulos, G. (2002). Locus control regions. Blood 100: 3077-3086 [Abstract] [Full Text]  
  • Harju, S., McQueen, K. J., Peterson, K. R. (2002). Chromatin Structure and Control of {beta}-Like Globin Gene Switching. Exp. Biol. Med. 227: 683-700 [Abstract] [Full Text]  
  • Farrell, C. M., West, A. G., Felsenfeld, G. (2002). Conserved CTCF Insulator Elements Flank the Mouse and Human {beta}-Globin Loci. Mol. Cell. Biol. 22: 3820-3831 [Abstract] [Full Text]  
  • Li, Q., Zhang, M., Han, H., Rohde, A., Stamatoyannopoulos, G. (2002). Evidence that DNase I hypersensitive site 5 of the human {beta}-globin locus control region functions as a chromosomal insulator in transgenic mice. Nucleic Acids Res 30: 2484-2491 [Abstract] [Full Text]  
  • Navas, P. A., Li, Q., Peterson, K. R., Swank, R. A., Rohde, A., Roy, J., Stamatoyannopoulos, G. (2002). Activation of the {beta}-like globin genes in transgenic mice is dependent on the presence of the {beta}-locus control region. Hum Mol Genet 11: 893-903 [Abstract] [Full Text]  
  • Blobel, G. A. (2002). CBP and p300: versatile coregulators with important roles in hematopoietic gene expression. J. Leukoc. Biol. 71: 545-556 [Full Text]  
  • Lotti, F., Menguzzato, E., Rossi, C., Naldini, L., Ailles, L., Mavilio, F., Ferrari, G. (2002). Transcriptional Targeting of Lentiviral Vectors by Long Terminal Repeat Enhancer Replacement. J. Virol. 76: 3996-4007 [Abstract] [Full Text]  
  • Lorincz, M. C., Schubeler, D., Groudine, M. (2001). Methylation-Mediated Proviral Silencing Is Associated with MeCP2 Recruitment and Localized Histone H3 Deacetylation. Mol. Cell. Biol. 21: 7913-7922 [Abstract] [Full Text]  
  • Plant, K. E., Routledge, S. J. E., Proudfoot, N. J. (2001). Intergenic Transcription in the Human {beta}-Globin Gene Cluster. Mol. Cell. Biol. 21: 6507-6514 [Abstract] [Full Text]  
  • Ortiz, B. D., Harrow, F., Cado, D., Santoso, B., Winoto, A. (2001). Function and Factor Interactions of a Locus Control Region Element in the Mouse T Cell Receptor-{alpha}/Dad1 Gene Locus. J. Immunol. 167: 3836-3845 [Abstract] [Full Text]  
  • Schubeler, D., Groudine, M., Bender, M. A. (2001). The murine beta -globin locus control region regulates the rate of transcription but not the hyperacetylation of histones at the active genes. Proc. Natl. Acad. Sci. USA 10.1073/pnas.201394698v1 [Abstract] [Full Text]  
  • Sawado, T., Igarashi, K., Groudine, M. (2001). Activation of beta -major globin gene transcription is associated with recruitment of NF-E2 to the beta -globin LCR and gene promoter. Proc. Natl. Acad. Sci. USA 10.1073/pnas.181344198v1 [Abstract] [Full Text]  
  • Kaufman, R. M., Lu, Z. H., Behl, R., Holt, J. M., Ackers, G. K., Ley, T. J. (2001). Lack of neighborhood effects from a transcriptionally active phosphoglycerate kinase-neo cassette located between the murine {beta}-major and {beta}-minor globin genes. Blood 98: 65-73 [Abstract] [Full Text]  
  • Molete, J. M., Petrykowska, H., Bouhassira, E. E., Feng, Y.-Q., Miller, W., Hardison, R. C. (2001). Sequences Flanking Hypersensitive Sites of the {beta}-Globin Locus Control Region Are Required for Synergistic Enhancement. Mol. Cell. Biol. 21: 2969-2980 [Abstract] [Full Text]  
  • Leach, K. M., Nightingale, K., Igarashi, K., Levings, P. P., Engel, J. D., Becker, P. B., Bungert, J. (2001). Reconstitution of Human {beta}-Globin Locus Control Region Hypersensitive Sites in the Absence of Chromatin Assembly. Mol. Cell. Biol. 21: 2629-2640 [Abstract] [Full Text]  
  • Farrell, C. M., Grinberg, A., Huang, S. P., Chen, D., Pichel, J. G., Westphal, H., Felsenfeld, G. (2000). A large upstream region is not necessary for gene expression or hypersensitive site formation at the mouse beta -globin locus. Proc. Natl. Acad. Sci. USA 97: 14554-14559 [Abstract] [Full Text]  
  • Bulger, M., Bender, M. A., van Doorninck, J. H., Wertman, B., Farrell, C. M., Felsenfeld, G., Groudine, M., Hardison, R. (2000). Comparative structural and functional analysis of the olfactory receptor genes flanking the human and mouse beta -globin gene clusters. Proc. Natl. Acad. Sci. USA 97: 14560-14565 [Abstract] [Full Text]  
  • Wei, W., Brennan, M. D. (2000). Polarity of transcriptional enhancement revealed by an insulator element. Proc. Natl. Acad. Sci. USA 10.1073/pnas.011529598v1 [Abstract] [Full Text]  
  • Cimbora, D. M., Schübeler, D., Reik, A., Hamilton, J., Francastel, C., Epner, E. M., Groudine, M. (2000). Long-Distance Control of Origin Choice and Replication Timing in the Human beta -Globin Locus Are Independent of the Locus Control Region. Mol. Cell. Biol. 20: 5581-5591 [Abstract] [Full Text]  
  • Forsberg, E. C., Downs, K. M., Bresnick, E. H. (2000). Direct interaction of NF-E2 with hypersensitive site 2 of the beta -globin locus control region in living cells. Blood 96: 334-339 [Abstract] [Full Text]  
  • Bender, M. A., Mehaffey, M. G., Telling, A., Hug, B., Ley, T. J., Groudine, M., Fiering, S. (2000). Independent formation of DnaseI hypersensitive sites in the murine beta -globin locus control region. Blood 95: 3600-3604 [Abstract] [Full Text]  
  • Rubin, J. E., Pasceri, P., Wu, X., Leboulch, P., Ellis, J. (2000). Locus control region activity by 5'HS3 requires a functional interaction with beta -globin gene regulatory elements: expression of novel beta /gamma -globin hybrid transgenes. Blood 95: 3242-3249 [Abstract] [Full Text]  
  • Schübeler, D., Francastel, C., Cimbora, D. M., Reik, A., Martin, D. I.K., Groudine, M. (2000). Nuclear localization and histone acetylation: a pathway for chromatin opening and transcriptional activation of the human beta -globin locus. Genes Dev. 14: 940-950 [Abstract] [Full Text]  
  • McDowell, J. C., Dean, A. (1999). Structural and Functional Cross-Talk between a Distant Enhancer and the varepsilon -Globin Gene Promoter Shows Interdependence of the Two Elements in Chromatin. Mol. Cell. Biol. 19: 7600-7609 [Abstract] [Full Text]  
  • Kaufman, R. M., Pham, C. T.N., Ley, T. J. (1999). Transgenic Analysis of a 100-kb Human beta -Globin Cluster-Containing DNA Fragment Propagated as a Bacterial Artificial Chromosome. Blood 94: 3178-3184 [Abstract] [Full Text]  
  • Bulger, M., Groudine, M. (1999). Looping versus linking: toward a model for long-distance gene activation. Genes Dev. 13: 2465-2477 [Full Text]  
  • Feng, Y.-Q., Alami, R., Bouhassira, E. E. (1999). Enhancer-Dependent Transcriptional Oscillations in Mouse Erythroleukemia Cells. Mol. Cell. Biol. 19: 4907-4917 [Abstract] [Full Text]  
  • Grande, A., Piovani, B., Aiuti, A., Ottolenghi, S., Mavilio, F., Ferrari, G. (1999). Transcriptional Targeting of Retroviral Vectors to the Erythroblastic Progeny of Transduced Hematopoietic Stem Cells. Blood 93: 3276-3285 [Abstract] [Full Text]  
  • Walters, M. C., Fiering, S., Bouhassira, E. E., Scalzo, D., Goeke, S., Magis, W., Garrick, D., Whitelaw, E., Martin, D. I. K. (1999). The Chicken beta -Globin 5'HS4 Boundary Element Blocks Enhancer-Mediated Suppression of Silencing. Mol. Cell. Biol. 19: 3714-3726 [Abstract] [Full Text]  
  • Bulger, M., von Doorninck, J. H., Saitoh, N., Telling, A., Farrell, C., Bender, M. A., Felsenfeld, G., Axel, R., Groudine, M. (1999). Conservation of sequence and structure flanking the mouse and human beta -globin loci: The beta -globin genes are embedded within an array of odorant receptor genes. Proc. Natl. Acad. Sci. USA 96: 5129-5134 [Abstract] [Full Text]  
  • Elnitski, L., Li, J., Noguchi, C. T., Miller, W., Hardison, R. (2001). A Negative Cis-element Regulates the Level of Enhancement by Hypersensitive Site 2 of the beta -Globin Locus Control Region. J. Biol. Chem. 276: 6289-6298 [Abstract] [Full Text]  
  • Wei, W., Brennan, M. D. (2000). Polarity of transcriptional enhancement revealed by an insulator element. Proc. Natl. Acad. Sci. USA 97: 14518-14523 [Abstract] [Full Text]  
  • Sawado, T., Igarashi, K., Groudine, M. (2001). Activation of beta -major globin gene transcription is associated with recruitment of NF-E2 to the beta -globin LCR and gene promoter. Proc. Natl. Acad. Sci. USA 98: 10226-10231 [Abstract] [Full Text]  
  • Schubeler, D., Groudine, M., Bender, M. A. (2001). The murine beta -globin locus control region regulates the rate of transcription but not the hyperacetylation of histones at the active genes. Proc. Natl. Acad. Sci. USA 98: 11432-11437 [Abstract] [Full Text]  


Copyright © 2009 by the American Society for Microbiology.   For an alternate route to Journals.ASM.org, visit: http://intl-journals.asm.org | More Info»