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Class II MHC proteins play central roles in controlling immune cell repertoire and responses. These roles depend on precise regulation of the level and cell-type specificity of class II gene expression. Instances of both coordinate and non-coordinate regulation of the multiple class II genes have been described. A 1.3 kb region of the class II MHC gene A alpha has previously been shown to activate transcription in a cell-type specific fashion that correlated with the expression of A alpha. The mouse A alpha gene differs from other class II MHC genes in that its conserved X region also contains the CRE/ATF DNA motif TGACGTCA. Substitution mutations were introduced into the 1.3 kb region such that the CRE/ATF (X2) motif was altered, but not the adjacent X1 or Y box motifs. Controls confirmed that these mutations eliminated the binding of nuclear proteins to the CRE/ATF motif and reduced transcriptional activity as much as mutation of the Y box. In addition, a new positive transcription element was identified far upstream from the conserved X-Y region, centered on position -970. The sequence of this region does not resemble previously described transcription elements or other MHC class II 5' flanking sequences. The activity of this element was absolutely dependent on the presence of the X-Y region. These data are most consistent with a model in which functionally important sequences unique to a single class II MHC gene can be intimately interposed between conserved MHC transcription elements, and non-consensus elements upstream from the conserved region contribute to control of A alpha.