On cue

Just like orchestra musicians waiting for their cue, RNA Polymerase II molecules are poised at the start site of many developmentally controlled genes, waiting for the signal to play their part in the genomic symphony.

An assembly of transcription elongation factors, known as the super elongation complex, or SEC, assists in triggering the paused RNA polymerases to start transcribing the gene ahead, found Stowers Investigator Ali Shilatifard’s team and their collaborators in Robb Krumlauf’s lab.

Transcriptional control by RNA polymerase II (pol II) is a tightly orchestrated, multi-step process that requires the concerted action of a large number of players to successfully transcribe the full length of genes. For many years, the initiation of transcription—the assembly of the basal transcription machinery at the start site—was considered the rate-limiting step. “We know now that the elongation step is a major node for the regulation of gene expression,” says Shilatifard, PhD. “In fact, we have shown that mislocated elongation factors are involved in the pathogenesis of infant acute lymphoblastic and mixed lineage leukemia.”

Mixed lineage leukemia is caused by a chromosomal translocation of the gene named MLL, resulting in its fusion to a seemingly random collection of other genes. Although the translocation partners don’t share any obvious similarities, they all create potent leukemia-causing hybrid genes. In an earlier study, Shilatifard and his colleagues had identified the SEC as the common denominator shared by all MLL-fusion proteins, explaining how the accidental activation of developmentally regulated genes as a result of these MLL translocations could lead to leukemia.

The study appeared in the July 15, 2011, issue of Genes & Development.