Friday, April 30, 2010

A Second Level of Gene Transcription Control

Controlling gene expression is an important key to controlling ageing, cancer, diseases of degeneration and autoimmunity, and virtually any other mechanism of human health and pathology. As scientist learn more about the mechanisms of gene expression, they also discover new ways of intervening to prevent or treat disease. The following article discusses the ongoing clarification of an important added complexity of gene expression that will certainly be exploited for good effect before long.
A new study published online today (April 29) in Cell helps drive home just how widespread this second level of gene control is, and implicates a cancer-causing transcription factor as a major player in the process.

"This is another piece in the puzzle that demonstrates controlling the elongation phase of transcription" -- the production of messenger RNA as the transcriptional apparatus propagates down the gene -- "is one of the more important control mechanisms," said biochemist David Price of the University of Iowa, who was not involved in the study. "[This] paper is going to help convince the field that this is just the way it is."

Scientists once believed that transcription factors promoted gene expression simply by recruiting RNA polymerase II (Pol II) machinery to the promoter region of their target genes, and letting the Pol II take over from there. But over the last 20 years, several lines of evidence indicated that once bound to the promoter, Pol II pauses, or stalls, just a little ways down the transcript, and needs another signal (such as a transcription factor) to continue transcribing the gene. Recent evidence suggests that this pause is a widespread phenomenon in the genome, but "there's been some reluctance in the transcription community to accept that there are these polymerases poised [just past the start site] all throughout the human genome," Price said.

Exploring the role of this mechanism of gene control in mouse embryonic stem cells (ESCs), molecular biologist Richard Young of the Whitehead Institute for Biomedical Research and Massachusetts Institute of Technology and his colleagues have all but eliminated that doubt. They found evidence of paused polymerases on the vast majority of genes -- both those actively being transcribed and those that remained silent.

"We're thinking now that at all genes where RNA polymerase II initiates transcription, there is a pause step," Young said. "So even genes that are being currently and actively transcribed, polymerase initiates [transcription], but must go through this pause checkpoint before it's allowed to proceed to elongation."

The team further showed that the well-studied transcription factor c-Myc, which is involved in cell self-renewal and proliferation and has been implicated in 15-30 percent of human cancers, is an example of the additional factor needed to push Pol II past the pause. Instead of promoting gene expression by recruiting Pol II to the genes, c-Myc appears to release already-initiated polymerases from this paused stage. It does so by recruiting a protein known as positive transcription elongation factor b (P-TEPb) to release the Pol II to finish what it started.

Understanding the details of this mechanism of gene control could thus have important implications for the treatment of a variety of ailments, said molecular biologist and clinician B. Matija Peterlin of the University of California, San Francisco, who also did not participate in the research. "I think it brings a whole new aspect to not just cancer [research] but" other diseases as well, Peterlin said. "If you attenuate the activity of P-TEFb, you might be able to [develop] a non-gene-modifying way treat a lot of human diseases."

P.B. Rahl, et al., "c-Myc regulates transcriptional pause release," Cell:141,1-14,2010.

Read more: More support for transcription trick - The Scientist - Magazine of the Life Sciences _the-scientist



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