The role of Brg1, a catalytic subunit of mammalian chromatin-remodeling complexes, in T cell development.
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.
Gebuhr
Thomas C
TC
Department of Genetics, University of North Carolina, Chapel Hill, NC 27599, USA.
Kovalev
Grigoriy I
GI
Bultman
Scott
S
Godfrey
Virginia
V
Su
Lishan
L
Magnuson
Terry
T
D000818:Animals; D017209:Apoptosis; D015704:CD4 Antigens / Q000032:analysis; D016827:CD8 Antigens / Q000032:analysis; D018797:Cell Cycle Proteins / Q000032:analysis; D004265:DNA Helicases; D029721:Drosophila Proteins; D016481:Helicobacter Infections / Q000150:complications; D008213:Lymphocyte Activation; D051379:Mice; D009687:Nuclear Proteins / Q000502:physiology*; D016692:Receptors, Antigen, T-Cell, gamma-delta / Q000032:analysis; D012005:Rectal Prolapse / Q000209:etiology; D013601:T-Lymphocytes / Q000502:physiology*; D013950:Thymus Gland / Q000502:physiology; D015534:Trans-Activators / Q000032:analysis; D014157:Transcription Factors / Q000502:physiology*
D015704:CD4 Antigens; D016827:CD8 Antigens; D018797:Cell Cycle Proteins; D029721:Drosophila Proteins; D009687:Nuclear Proteins; D016692:Receptors, Antigen, T-Cell, gamma-delta; D015534:Trans-Activators; D014157:Transcription Factors; C086469:brm protein, Drosophila; C513194:Smarca4 protein, mouse; D004265:DNA Helicases