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/Dad1 Gene Locus1
*
Department of Biological Sciences, City University of New York, Hunter College, New York, NY 10021; and
Department of Molecular and Cell Biology, Cancer Research Laboratory, and Division of Immunology, University of California, Berkeley, CA 94720.
Locus control regions (LCRs) refer to cis-acting
elements composed of several DNase I hypersensitive sites, which
synergize to protect transgenes from integration-site dependent effects
in a tissue-specific manner. LCRs have been identified in many
immunologically important gene loci, including one between the
TCR
/TCR
gene segments and the ubiquitously
expressed Dad1 gene. Expression of a transgene
under the control of all the LCR elements is T cell specific. However,
a subfragment of this LCR is functional in a wide variety of tissues.
How a ubiquitously active element can participate in tissue-restricted
LCR activity is not clear. In this study, we localize the ubiquitously
active sequences of the TCR- LCR to an 800-bp region containing a
prominent DNase hypersensitive site. In isolation, the activity in this
region suppresses position effect transgene silencing in many tissues.
A combination of in vivo footprint examination of this element in
widely active transgene and EMSAs revealed tissue-unrestricted factor
occupancy patterns and binding of several ubiquitously expressed
transcription factors. In contrast, tissue-specific, differential
protein occupancies at this element were observed in the endogenous
locus or full-length LCR transgene. We identified tissue-restricted
AML-1 and Elf-1 as proteins that potentially act via this element.
These data demonstrate that a widely active LCR module can synergize
with other LCR components to produce tissue-specific LCR activity
through differential protein occupancy and function and provide
evidence to support a role for this LCR module in the regulation of
both TCR and Dad1 genes.
This article has been cited by other articles:
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  J. Gomos-Klein, F. Harrow, J. Alarcon, and B. D. Ortiz CTCF-Independent, but Not CTCF-Dependent, Elements Significantly Contribute to TCR-{alpha} Locus Control Region Activity J. Immunol., July 15, 2007; 179(2): 1088 - 1095. [Abstract] [Full Text] [PDF]
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F. Harrow and B. D. Ortiz The TCR{alpha} Locus Control Region Specifies Thymic, But Not Peripheral, Patterns of TCR{alpha} Gene Expression J. Immunol., November 15, 2005; 175(10): 6659 - 6667. [Abstract] [Full Text] [PDF]
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 F. Magdinier, T. M. Yusufzai, and G. Felsenfeld Both CTCF-dependent and -independent Insulators Are Found between the Mouse T Cell Receptor {alpha} and Dad1 Genes J. Biol. Chem., June 11, 2004; 279(24): 25381 - 25389. [Abstract] [Full Text] [PDF]
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F. Harrow, J. U. Amuta, S. R. Hutchinson, F. Akwaa, and B. D. Ortiz Factors Binding a Non-classical Cis-element Prevent Heterochromatin Effects on Locus Control Region Activity J. Biol. Chem., April 23, 2004; 279(17): 17842 - 17849. [Abstract] [Full Text] [PDF]
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 M. Bulger, D. Schubeler, M. A. Bender, J. Hamilton, C. M. Farrell, R. C. Hardison, and M. Groudine A Complex Chromatin Landscape Revealed by Patterns of Nuclease Sensitivity and Histone Modification within the Mouse {beta}-Globin Locus Mol. Cell. Biol., August 1, 2003; 23(15): 5234 - 5244. [Abstract] [Full Text] [PDF]
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 Q. Li, K. R. Peterson, X. Fang, and G. Stamatoyannopoulos Locus control regions Blood, October 16, 2002; 100(9): 3077 - 3086. [Abstract] [Full Text] [PDF]
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