Reciprocal regulation of CD4/CD8 expression by SWI/SNF-like BAF complexes.
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 defined. 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 vitro, 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 switching.
Department of Pathology and Developmental Biology, Howard Hughes Medical Institute, Stanford University Medical School, Palo Alto, California 94305, USA.
Tian H
TH
Chi
Mimi
M
Wan
Keji
K
Zhao
Ichiro
I
Taniuchi
Lei
L
Chen
Dan R
DR
Littman
Gerald R
GR
Crabtree
D000818:Animals; D015704:CD4 Antigens / Q000096:biosynthesis* / Q000235:genetics / Q000378:metabolism; D016827:CD8 Antigens / Q000096:biosynthesis* / Q000235:genetics / Q000378:metabolism; D002843:Chromatin / Q000378:metabolism; D003432:Cross-Linking Reagents; D004265:DNA Helicases; D004268:DNA-Binding Proteins / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D005434:Flow Cytometry; D005786:Gene Expression Regulation; D020868:Gene Silencing; D046911:Macromolecular Substances; D051379:Mice; D008822:Mice, Transgenic; D009154:Mutation / Q000235:genetics; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D021122:Protein Subunits; D013950:Thymus Gland / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism
D015704:CD4 Antigens; D016827:CD8 Antigens; D002843:Chromatin; D003432:Cross-Linking Reagents; D004268:DNA-Binding Proteins; D046911:Macromolecular Substances; D009687:Nuclear Proteins; D021122:Protein Subunits; D014157:Transcription Factors; C513194:Smarca4 protein, mouse; D004265:DNA Helicases