© 1989 by The Society for Integrative and Comparative Biology
A Conceptual View of Transcriptional Regulation1
Department of Biochemistry and Biophysics, University of California San Franasco, California 94143-0448
Recent studies seem to imply that the regulation of transcription might proceed by several distinct mechanisms. Promoters, the DNA sequences at which RNA polymerase binds and initiates transcription, appear to be organized entirely differently in prokaryotes and eukaryotes. Moreover, the classical studies of transcription regulation in prokaryotes had established a "short range" paradigm in which regulatory proteins bind to DNA sequences contiguous with the promoter, and modulate initiation efficiency by directly contacting RNA polymerase. More recently, a "long range" mechanism was discovered in eukaryotes in which regulatory proteins exert their effects from remote DNA sites, termed enhancers or long range operators, which can be thousands of base pairs from their target promoters; long range regulation has now been described in prokaryotes as well. In fact, all of these apparently disparate strategies may operate according to a common general principle in which activity is determined by specific proteinprotein interactions. In particular, I suggest that the different schemes for promoter function and regulation may be distinguished only by differences in their relative dependence upon protein-DNA interactions to facilitate appropriate protein-protein alignments.
Long range regulation of gene expression suggests a simple and efficient way to evolve new regulatory circuits: stochastic germ line transpositions of long range regulatory elements could readily influence the activities of nearby promoters. Indeed, certain enhancers and long range operators have been found to reside on transposable DNA elements. For transpositions with favorable consequences, secondary rearrangements would subsequently move the regulatory element closer to the promoter, eventually yielding a short range regulatory mechanism. Thus, long range and short range regulation may be mechanistically and evolutionarily related, perhaps explaining why the two schemes persist and often coexist even within a single cell. Long range regulatory mechanisms, according to this view, provide a primary driving force for regulatory evolution.