Did you know that the genetic production process (gene expression) can be paused? A few years ago, most geneticists didn’t know either, and now it appears that the ability to pause genetic expression is not limited to a handful of genes (as originally thought) and may be a general capability for cells at all stages of development. That’s the conclusion of a study published in the journal Cell by a team of researchers led by Richard Young of the Whitehead Institute and the Massachusetts Institute of Technology (USA).
The analogy used is ‘like pausing a DVR.’ That’s really crude, but then this is something relatively new and incomplete in terms of scientific knowledge (read: more experimentation is needed as well as verification and debate). Nevertheless, the notion that there is a kind of third-state for gene expression (on, off, paused) has lots of intriguing ramifications.
The nitty-gritty of the research is at the molecular level: The process starting with genes in cell nucleus DNA and finishing with production of proteins coded by those genes has many steps. The first big step is the transcription (re-writing) of gene information onto messenger RNA (mRNA) to be transported out of the nucleus into the rest of the cell. This first step is known to involve what are called promoters, molecules that act like a kind of Velcro to attach polymerase (protein) enzymes to the DNA, before the enzymes copy the DNA information to the mRNA.
Using embryonic stem cells for a genome-wide analysis, it was discovered that while promoters and enzymes were found around the DNA all the time, so too were factors that are known to pause the binding of the enzymes. Two of these factors (called DSIF and NELF) are there to temporarily halt the binding process – in effect, pause it – and then other factors, in particular c-Myc, release the pause, turning the gene back ‘on.’
The researchers thought the pausing factors would be specific to certain genes, but their experiments showed that pausing was occurring in 75% of all promoter transcriptions. Because pausing is not limited to developmental genes, the researchers now believe that all genes may be involved and in many types of cells. The next big question is why:
Young said he thinks this second layer of control likely offers cells some added flexibility. In some cases, he notes, this sort of pausing seems to allow a rapid response to particular cues. The pause function might also be necessary, he says, because polymerases can be surprisingly sloppy in doing their jobs. The enzymes will often transcribe in two directions, one of them clearly backwards.
“It’s a little clueless,” Young said. “Pause control may be a way of ensuring that transcription continues only in the correct direction, and at real genes instead of willy-nilly.”
Most of this is informed speculation. The role of pausing in the transcription process is wide open for interpretation at this point, and of course, much more experimental work. Still, the idea that there is a reason for the pause capability indicates that the molecular chemistry involved has some very important pathways – pathways that could be manipulated. In particular, the role of c-Myc, infamously associated with cancer, may provide insights into not only healthy DNA transcription but also damaged, cancerous processes.