Reciprocal regulation of CD4/CD8 expression by SWI/SNF-like BAF complexes

Abstract

Thymic development produces two sub-lineages of T cells expressing either CD4 or CD8 co-receptors that assist antibody production and mediate cell killing, respectively. The mechanisms for mutually exclusive co-receptor expression remain poorly defined1,2. We find that mutations in the high mobility group (HMG) domain of BAF57—a DNA-binding subunit of the mammalian SWI/SNF-like chromatin-remodelling BAF complexes—or in the BAF complex ATPase subunit Brg, impair both CD4 silencing and CD8 activation. Brg is haploinsufficient for CD8 activation, but not for CD4 silencing, whereas BAF57 mutations preferentially impair CD4 silencing, pointing to target- and subunit-specific mechanisms of chromatin remodelling. BAF complexes directly bind the CD4 silencer, but the BAF57 HMG domain is dispensable for tethering BAF complexes to the CD4 silencer or other chromatin loci in vivo, or for remodelling reconstituted templates in vitro3,4, suggesting that chromatin remodelling in vivo requires HMG-dependent DNA bending. These results indicate that BAF complexes contribute to lineage bifurcation by reciprocally regulating lineage-specific genes, reminiscent of the role of the yeast SWI/SNF complex in mediating mating-type switching5,6.

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Figure 1: The BAF57 transgenes suppressed endogenous BAF57 expression and produce BAF complexes deficient in HMG functions.
Figure 2: BAF complexes are required for thymic development.
Figure 3: Reciprocal CD4 and CD8 misregulation in the BAF mutants.
Figure 4: BAF complexes bind the CD4 silencer independently of the BAF57 HMG domain.

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Acknowledgements

We thank C. Wilson for encouragement and comments; K. Akashi for help with FACS during the early course of the work; K. Stankunas, J. Owen, A. Singer, I. Graef, K. Neu and C. Forsberg for critical readings of the manuscript; T. Magnuson for Brg null mice before publication; R. Perlmutter for Lck promoter constructs; and H. Liu for technical help. T.C. is supported by a fellowship from Leukemia and Lymphoma Society of America. G.R.C. is a HHMI investigator. These studies were funded by a grant from the National Institute of Health.

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Correspondence to Gerald R. Crabtree.

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Chi, T., Wan, M., Zhao, K. et al. Reciprocal regulation of CD4/CD8 expression by SWI/SNF-like BAF complexes. Nature 418, 195–199 (2002). https://doi.org/10.1038/nature00876

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