Analysis of the immunoglobulin gene suggests that their expression is controlled through the combinatorial action of tissue- and stage-specific factors (OTF-2, TF-microB, NF-kappa B), as well as more widely expressed E motif-binding factors such as E47/E12. Two basic issues cloud understanding of how these factors are involved in immunoglobulin gene regulation. First, cloning of these factors shows them to be members of families of proteins, all with similar DNA-binding specificities. OTF-2 is a member of the POU domain family, NF-kappa B is a related protein, and the microE5/kappa E2-binding factors are members of the bHLH family. Second, these binding sites and associated factors are involved in the regulation of many genes, not only the immunoglobulin genes, and in fact not only lymphoid-specific genes. These facts complicate understanding which member of a family is in fact responsible for interaction with, and activation of, a particular binding element in an enhancer/promoter. Recently, more detailed analysis of the interactions between such proteins and their related binding sites suggest that a certain level of specificity may in fact be encoded by the DNA element such that one family member of a protein is preferentially bound, or alternatively that the protein-DNA interactions that occur give subtle alterations in protein conformation that unmask an activation or protein-protein interactive domain. An additional level of regulation is imparted by combinatorial mechanisms such as adjacent DNA-binding elements and factors that may alter activity, as well as "cofactors" that, by forming a complex with the bound factor, affect its activation of a gene in a particular cell type. A third level of specificity may be obtained by factors such as NF-kappa B and the bHLH family due to their ability to create heterogeneous complexes, creating unique complexes in a tissue- or stage-specific manner. The multiple functions transcription factors such as NF-kappa B and OTF-2 play in the transcriptional regulation of multiple genes seems complex in contrast to a one factor, one gene regulation model. However, this type of organization may limit the number of factors lymphocytes would require if each lymphoid-specific gene were activated by a unique factor. Thus what appears to be complexity at the molecular level may reflect an economical organization at the cellular level. Investigation of the key factors controlling these genes suggests an ordered cascade of transcription factors becomes available in the cell during B cell differentiation.(ABSTRACT TRUNCATED AT 400 WORDS)