Watching Genes Loop the Loop

Most cells of a given species contain essentially the same complement of genes, yet individual genetically identical cells can assume dramatically different appearances and behaviours. This is achieved largely by the regulation of the transcription of individual genes, orchestrated by the specific binding of proteins to nearby sites in the genome—a principle first recognised 50 years ago by François Jacob (who just died this April) and Jacques Monod from their work on the paradigmatic lac operon in Escherichia coli. François Jacob went on to establish the second textbook workhorse of transcriptional regulation—the lambda repressor system. Bacteriophage lambda is a virus that infects E. coli but then makes a twoway decision to either take a nap in the host genome or to ‘‘go viral’’ and burst the cell, releasing a hundred or so bacteriophage babies (lysogeny versus lysis, in the parlance). The dormant lysogenic phase can be perpetuated stably for many bacterial generations, and is maintained by the binding of the lambda repressor to the phage genome (now lodged within the host bacterial genome). But this is where it emerged that genes aren’t only regulated by the binding of proteins to sites in their immediate vicinity, as is the case of the simple lac operon. Instead, in many cases, sites a considerable distance away can also influence the decision whether to transcribe or not to transcribe a gene. The lambda repressor molecules in fact bind to two separate regions in the phage genome that are 2.3 kilobases apart (about 700 nm on a straight DNA molecule, about 200 nm on average in solution, and substantially less inside a real live bacterium). Direct interactions between the two clusters of lambda repressors are then assumed to cause looping of the intervening DNA, bringing the two previously distant sites together. This shuts down almost all phage transcription but enhances transcription of the repressor gene, which lies next to one of the two sites, thereby making more