The Journal of Experimental Medicine
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Published 15 December 2003. doi:10.1084/jem.20030714
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© Rockefeller University Press, 0022-1007/2003/12/1937 $5.00
The Journal of Experimental Medicine, Volume 198, Number 12, 1937-1949

The Role of Brg1, a Catalytic Subunit of Mammalian Chromatin-remodeling Complexes, in T Cell Development

Thomas C. Gebuhr1, Grigoriy I. Kovalev2,4, Scott Bultman1, Virginia Godfrey3, Lishan Su2,4 and Terry Magnuson1,4,5

1 Department of Genetics, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599
2 Department of Microbiology and Immunology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599
3 Department of Pathology and Laboratory Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599
4 Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599
5 Carolina Center for Genome Sciences, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599

Address correspondence to Terry Magnuson, Department of Genetics, Neurosciences Research Building, Room 4109D, University of North Carolina, CB 7264, 103 Mason Farm Road, Chapel Hill, NC 27599. Phone: (919) 843-6475; Fax: (919) 843-6365; email: trm4{at}med.unc.edu

Mammalian SWI–SNF-related complexes use brahma-related gene 1 (Brg1) as a catalytic subunit to remodel nucleosomes and regulate transcription. Recent biochemical data has linked Brg1 function to genes important for T lymphocyte differentiation. To investigate the role of SWI–SNF-related complexes in this lineage, we ablated Brg1 function in T lymphocytes. T cell–specific Brg1-deficient mice showed profound thymic abnormalities, CD4 derepression at the double negative (DN; CD4- CD8-) stage, and a developmental block at the DN to double positive (CD4+ CD8+) transition. 5'-bromo-2'-deoxyuridine incorporation and annexin V staining establish a role for Brg1 complexes in the regulation of thymocyte cell proliferation and survival. This Brg1-dependent cell survival is specific for developing thymocytes as indicated by the presence of Brg1-deficient mature T lymphocytes that have escaped the developmental block in the thymus. However, reductions in peripheral T cell populations lead to immunodeficiency and compromised health of mutant mice. These results highlight the importance of chromatin-remodeling complexes at different stages in the development of a mammalian cell lineage.

Key Words: Brg1 • SWI–SNF • chromatin • T cell • development

T.C. Gebuhr and G.I. Kovalev contributed equally to this work.

The online version of this article contains supplemental material.

Abbreviations used in this paper: BrdU, 5'-bromo-2'-deoxyuridine; Brg1, brahma-related gene 1; Brm, brahma; DN, double negative; DP, double positive; PI, propidium iodide; SP, single positive; TN, triple negative.


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