USING ALTERED SPECIFICITY OCT-1 AND OCT-2 MUTANTS TO ANALYZE THE REGULATION OF IMMUNOGLOBULIN GENE-TRANSCRIPTION

Oct-1 and Oct-2 represent the prototypical example of related transcri ption factors with identical DNA recognition properties, They bind fun ctionally critical octamer elements found in diverse regulatory sequen ces, It has not been possible to determine directly if these factors a re functionally redundant or selective when interacting with different regulatory sequences in the appropriate cell type. An equivalent pair of altered DNA-binding specificity mutants of Oct-1 and Oct-2 are use d to examine their function from varied regulatory contexts in B cells , These factors function as redundant activators of immunoglobulin (Ig ) gene promoters (V-kappa and V-H) and a histone H2B promoter, The str uctural basis of redundancy resides in the highly conserved DNA-bindin g POU domain, because this domain of either protein can activate trans cription from both Ig and H2B promoters, We find that the nature of a distal enhancer dictates the relative potency of Oct-1 versus Oct-2 bo und to a promoter, Oct-1 preferentially stimulates transcription from a V-H or V kappa promoter in combination with enhancers from the IgH o r Ig kappa locus, respectively, In this context, the more potent actio n of Oct-1 is dependent on a region external to the POU domain, These results suggest that Oct-1 may be the critical regulator of Ig gene tr anscription during B cell development and provide an explanation for s elective Ig isotype expression defects in Oct-2 and OCA-B null mice.