Yin Yang 1, Oct1, and NFAT-4 form repeating, cyclosporin-sensitive regulatory modules within the murine CD21 intronic control region.
The murine complement receptor type 2 gene (Cr2/CD21) is expressed by murine B and follicular dendritic cells, but not murine T cells. We have previously shown that appropriate transcriptional control of the CD21 gene requires the CD21 promoter as well as intronic sequences. We have also demonstrated that altering chromatin structure by inhibiting histone deacetylases induces CD21 expression in murine T cells by increasing the accessibility of promoter and intronic regulatory elements. In this report, we identify seven distinct regulatory areas within the first intron of the murine CD21 gene that are conserved between mouse and human CD21 intronic sequences. EMSA competition and supershift analyses reveal the formation of multiple DNA-protein complexes at these sites that include Yin Yang 1, Oct1, and NFAT-4. NFAT-containing complexes were altered in B cells treated with the NFAT inhibitor cyclosporin A and correlated with a repression of CD21 gene transcription implicating NFAT transcriptional control. Functional data revealed that no single region conferred cell-specific reporter gene expression, but rather the entire CD21 regulatory element was required to confer cell-specific gene expression. Taken together, these data demonstrate the formation of repeating, overlapping regulatory modules, all of which are required to coordinately control the cell-specific expression of the murine CD21 gene. We propose a model in which Yin Yang 1 and Oct1 may recruit histone deacetylase to multiple sites in the CD21 intronic regulatory element in nonexpressing cells and NFAT either displaces this histone deacetylase or recruits a histone acetylase to allow the formation of a functional transcriptional complex in expressing cells.
Zabel
Mark D
MD
Department of Pathology, Division of Cell Biology and Immunology, University of Utah School of Medicine, Salt Lake City, UT 84132, USA.
Wheeler
Wells
W
Weis
Janis J
JJ
Weis
John H
JH
D000818:Animals; D001402:B-Lymphocytes / Q000187:drug effects / Q000378:metabolism; D001483:Base Sequence; D001665:Binding Sites / Q000187:drug effects / Q000235:genetics / Q000276:immunology; D016572:Cyclosporine / Q000494:pharmacology*; D004268:DNA-Binding Proteins / Q000235:genetics* / Q000378:metabolism; D050981:Erythroid-Specific DNA-Binding Factors; D005786:Gene Expression Regulation / Q000187:drug effects / Q000276:immunology; D006801:Humans; D007438:Introns / Q000187:drug effects / Q000276:immunology*; D019901:Locus Control Region / Q000187:drug effects / Q000276:immunology*; D051379:Mice; D008969:Molecular Sequence Data; D050778:NFATC Transcription Factors; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism; D027702:Organic Cation Transporter 1 / Q000235:genetics* / Q000378:metabolism; D017464:Receptors, Complement 3d / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000235:genetics*; D012091:Repetitive Sequences, Nucleic Acid / Q000187:drug effects*; D012689:Sequence Homology, Nucleic Acid; D013601:T-Lymphocytes / Q000187:drug effects / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics* / Q000378:metabolism; D014407:Tumor Cells, Cultured; D050986:YY1 Transcription Factor
D004268:DNA-Binding Proteins; D050981:Erythroid-Specific DNA-Binding Factors; D050778:NFATC Transcription Factors; C494008:NFATC3 protein, human; C494009:Nfatc3 protein, mouse; D009687:Nuclear Proteins; D027702:Organic Cation Transporter 1; D017464:Receptors, Complement 3d; D014157:Transcription Factors; D050986:YY1 Transcription Factor; D016572:Cyclosporine