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

An enhancer/locus control region is not sufficient to open chromatin.

Diabetes Branch, National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, Maryland 20892.

ABSTRACT

To study the way in which an enhancer/locus control region (LCR) activates chromatin, we examined transgenic mice carrying various combinations of the chicken beta A-globin gene coding region, promoter, and 3' enhancer/LCR. We compared lines carrying only the coding region and enhancer R (E) and only the coding region and promoter (P) with those containing all three elements (PE). We have shown previously that all PE mice transcribe the transgene in a copy number-dependent manner while the P mice do not express their transgene. In the current study, we examined chromatin activation by monitoring formation of erythroid-specific hypersensitive sites at the promoter and enhancer. We found that all of the PE lines but none of the P lines show hypersensitivity. In contrast, only three of six E lines are hypersensitive (two strongly and one weakly), demonstrating position dependence of this transgene. The two E lines with strong hypersensitive sites were found also to have RNA complementary to the transgene, presumably starting from an adjacent adventitious mouse promoter. In all of these lines, we found a correlation between erythroid-specific hypersensitivity and erythroid-specific general DNase I sensitivity, an indicator of regional chromatin activation. The results support a mutual interaction model for the mechanism of chromatin opening by LCRs in which the enhancer/LCR and promoter must cooperate in order to generate open chromatin. The data are not consistent with a dominant enhancer model in which the enhancer/LCR can open chromatin autonomously.

This article has been cited by other articles:

• Hu, X., Bulger, M., Bender, M. A., Fields, J., Groudine, M., Fiering, S. (2006). Deletion of the core region of 5' HS2 of the mouse {beta}-globin locus control region reveals a distinct effect in comparison with human {beta}-globin transgenes. Blood 107: 821-826 [Abstract] [Full Text]  
• Xiang, P., Han, H., Barkess, G., Olave, I., Fang, X., Yin, W., Stamatoyannopoulos, G., Li, Q. (2005). Juxtaposition of the HPFH2 enhancer is not sufficient to reactivate the {gamma}-globin gene in adult erythropoiesis. Hum Mol Genet 14: 3047-3056 [Abstract] [Full Text]  
• Sabo, P. J., Hawrylycz, M., Wallace, J. C., Humbert, R., Yu, M., Shafer, A., Kawamoto, J., Hall, R., Mack, J., Dorschner, M. O., McArthur, M., Stamatoyannopoulos, J. A. (2004). Discovery of functional noncoding elements by digital analysis of chromatin structure. Proc. Natl. Acad. Sci. USA 101: 16837-16842 [Abstract] [Full Text]  
• Sabo, P. J., Humbert, R., Hawrylycz, M., Wallace, J. C., Dorschner, M. O., McArthur, M., Stamatoyannopoulos, J. A. (2004). Genome-wide identification of DNaseI hypersensitive sites using active chromatin sequence libraries. Proc. Natl. Acad. Sci. USA 101: 4537-4542 [Abstract] [Full Text]  
• Tanamachi, D. M., Moniot, D. C., Cado, D., Liu, S. D., Hsia, J. K., Raulet, D. H. (2004). Genomic Ly49A Transgenes: Basis of Variegated Ly49A Gene Expression and Identification of a Critical Regulatory Element. J. Immunol. 172: 1074-1082 [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]  
• Li, Q., Peterson, K. R., Fang, X., Stamatoyannopoulos, G. (2002). Locus control regions. Blood 100: 3077-3086 [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]  
• Duan, Z., Stamatoyannopoulos, G., Li, Q. (2001). Role of NF-Y in In Vivo Regulation of the {gamma}-Globin Gene. Mol. Cell. Biol. 21: 3083-3095 [Abstract] [Full Text]  
• Fernández, L. A., Winkler, M., Grosschedl, R. (2001). Matrix Attachment Region-Dependent Function of the Immunoglobulin {micro} Enhancer Involves Histone Acetylation at a Distance without Changes in Enhancer Occupancy. Mol. Cell. Biol. 21: 196-208 [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]  
• 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]  
• 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]  
• Baker, J. E., Kang, J., Xiong, N., Chen, T., Cado, D., Raulet, D. H. (1999). 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. Exp. Med. 190: 669-680 [Abstract] [Full Text]  
• Lee, J.-S., Lee, C.-H., Chung, J. H. (1999). The beta -globin promoter is important for recruitment of erythroid Kruppel-like factor to the locus control region in erythroid cells. Proc. Natl. Acad. Sci. USA 96: 10051-10055 [Abstract] [Full Text]  
• Moitra, J., Mason, M. M., Olive, M., Krylov, D., Gavrilova, O., Marcus-Samuels, B., Feigenbaum, L., Lee, E., Aoyama, T., Eckhaus, M., Reitman, M. L., Vinson, C. (1998). Life without white fat: a transgenic mouse. Genes Dev. 12: 3168-3181 [Abstract] [Full Text]  
• Reik, A., Telling, A., Zitnik, G., Cimbora, D., Epner, E., Groudine, M. (1998). 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. Mol. Cell. Biol. 18: 5992-6000 [Abstract] [Full Text]  
• Chen, X., Reitman, M., Bieker, J. J. (1998). Chromatin Structure and Transcriptional Control Elements of the Erythroid Kruppel-like Factor (EKLF) Gene. J. Biol. Chem. 273: 25031-25040 [Abstract] [Full Text]  
• Yu, S., Yu, D., Lee, E., Eckhaus, M., Lee, R., Corria, Z., Accili, D., Westphal, H., Weinstein, L. S. (1998). Variable and tissue-specific hormone resistance in heterotrimeric Gs protein alpha -subunit (Gsalpha ) knockout mice is due to tissue-specific imprinting of the Gsalpha gene. Proc. Natl. Acad. Sci. USA 95: 8715-8720 [Abstract] [Full Text]  
• Pasceri, P., Pannell, D., Wu, X., Ellis, J. (1998). Full Activity From Human beta -Globin Locus Control Region Transgenes Requires 5'HS1, Distal beta -Globin Promoter, and 3' beta -Globin Sequences. Blood 92: 653-663 [Abstract] [Full Text]  
• Blackwood, E. M., Kadonaga, J. T. (1998). Going the Distance: A Current View of Enhancer Action. Science 281: 60-63 [Abstract] [Full Text]  
• Scholz, H., Bossone, S. A., Cohen, H. T., Akella, U., Strauss, W. M., Sukhatme, V. P. (1997). A Far Upstream Cis-element Is Required for Wilms' Tumor-1 (WT1) Gene Expression in Renal Cell Culture. J. Biol. Chem. 272: 32836-32846 [Abstract] [Full Text]  
• Barton, M. C., Madani, N., Emerson, B. M. (1997). Distal enhancer regulation by promoter derepression in topologically constrained DNA in vitro. Proc. Natl. Acad. Sci. USA 94: 7257-7262 [Abstract] [Full Text]  
• Jagle, U., Muller, A. M., Kohler, H., Bonifer, C. (1997). Role of Positive and Negative Cis-regulatory Elements in the Transcriptional Activation of the Lysozyme Locus in Developing Macrophages of Transgenic Mice. J. Biol. Chem. 272: 5871-5879 [Abstract] [Full Text]  
• Chan, F.-Y., Robinson, J., Brownlie, A., Shivdasani, R. A., Donovan, A., Brugnara, C., Kim, J., Lau, B.-C., Witkowska, H. E., Zon, L. I. (1997). Characterization of Adult alpha - and beta -Globin Genes in the Zebrafish. Blood 89: 688-700 [Abstract] [Full Text]  
• Mason, M. M., Grasso, J. A., Gavrilova, O., Reitman, M. (1996). Identification of Functional Elements of the Chicken epsilon -Globin Promoter Involved in Stage-specific Interaction with the beta /epsilon Enhancer. J. Biol. Chem. 271: 25459-25467 [Abstract] [Full Text]  
• Babichuk, C. K., Duggan, B. L., Bleackley, R. C. (1996). In Vivo Regulation of Murine Granzyme B Gene Transcription in Activated Primary T Cells. J. Biol. Chem. 271: 16485-16493 [Abstract] [Full Text]  
• Tewari, R, Gillemans, N, Harper, A, Wijgerde, M, Zafarana, G, Drabek, D, Grosveld, F, Philipsen, S (1996). The human beta-globin locus control region confers an early embryonic erythroid-specific expression pattern to a basic promoter driving the bacterial lacZ gene. Development 122: 3991-3999 [Abstract]  
• Bungert, J, Dave, U, Lim, K C, Lieuw, K H, Shavit, J A, Liu, Q, Engel, J D (1995). Synergistic regulation of human beta-globin gene switching by locus control region elements HS3 and HS4.. Genes Dev. 9: 3083-3096 [Abstract]  
• Jenuwein, T, Forrester, W C, Qiu, R G, Grosschedl, R (1993). The immunoglobulin mu enhancer core establishes local factor access in nuclear chromatin independent of transcriptional stimulation.. Genes Dev. 7: 2016-2032 [Abstract]  
• 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]