Regulation of immunoglobulin gene transcription

Analysis of the immunoglobulin gene suggests that their expression is controlled through the combinatorial action of tissue- and stage-specific factors (OTF-2, TF-μB, NF-κB), 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-κB is a related protein, and the μE5/κE2-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 suggests 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-κB 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-κB 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. At least two factors, TF-μB and OTF-2, are required for the early expression of the heavy chain gene. Subsequent activation of the κ gene relies on the inducible factor NF-κB, which becomes constitutive in B cells. The switch from κ to λ gene activity occurs either through an as yet unidentified element and trans-acting factor, or perhaps through the λ enhancer μE2 site being activated by E47 homodimers made available on loss of Id expression in mature B cells. Of all these events, only one is sufficiently well understood at present to suggest a direct link between cell signaling and further differentiation. Posttranslational activation of the NF-κB protein suggests this factor may become available to activate the κ gene locus on physiological signaling of the pre-B cell. However, the initial events directing the onset of lymphoid differentiation, as well as the later developmental cues controlling κ inactivation and λ rearrangement and expression, remain to be elucidated.