CAMBRIDGE, Mass. (April 29, 2010) - A comprehensive new gene expression study in embryonic stem cells has uncovered a transcription control mechanism that is not only more pervasive than once thought but is also heavily regulated by the cancer-causing gene c-Myc.
In research published in the April 30th edition of Cell, a team of Whitehead Institute researchers describes a pausing step in the transcription process that serves to regulate expression of as many as 80% of the genes in mammalian cells.
Scientists have long known that DNA-binding transcription factors recruit the RNA polymerase Pol II (which prompts copying of DNA into mRNA protein codes) to promoters in order to kick off the transcription process. Now researchers in the lab of Whitehead Member Richard Young have found that additional factors recruited to the promoters serve to stop transcription in its tracks shortly after it's begun.
"It's like the engine's running, but the transmission is not engaged on that transcription apparatus," says Young, who is also a professor of biology at MIT. "You need something to engage that transmission."
It turns out that for a surprisingly large number of genes in embryonic stem cells, that "something" is the transcription factor c-Myc. This so-called pause release role for c-Myc is significant, as many of c-Myc's targets are genes in highly proliferative cells. Over-expression of c-Myc is a hallmark of a number of tumors, and it now appears that c-Myc's ability to release transcriptional pausing is linked with the hyper-proliferation that is characteristic of cancer cells.
"Our findings provide the molecular basis for loss of proliferation control in some cancers," says Peter Rahl, a postdoctoral researcher in Young's lab and first author of the Cell paper.
Armed with this new understanding of c-Myc's role in controlling proliferation genes, Young and his colleagues have embarked on a search for drugs that could interrupt c-Myc's pause-release activity in tumors where it's over-expressed.
"Clearly, cancer cells are able to exploit mechanisms that normally operate in embryonic stem cells," says Young, "so I expect further understanding of embryonic stem cell control mechanisms will give us additional insights into human disease mechanisms."
This research was supported by the National Institutes of Health (NIH) and National Cancer Institute (NCI).
Written by Nicole Giese
Richard Young's primary affiliation is with Whitehead Institute for Biomedical Research, where his laboratory is located and all his research is conducted. He is also a professor of biology at Massachusetts Institute of Technology.
"c-Myc regulates transcriptional pause release"
Cell, April 30, 2010.
Peter B. Rahl (1), Charles Y. Lin (1,2), Amy C. Seila (3,4), Ryan A. Flynn (3), Scott McCuine (1), Christopher B. Burge (2), Phillip A. Sharp (2,3), Richard A. Young (1,2)
1. Whitehead Institute for Biomedical Research, Cambridge, MA 02142
2. Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02142
3. Koch Institute, Massachusetts Institute of Technology, Cambridge, MA 02142
4. Present Address: Alnylam Pharmaceuticals, 300 Third Street, Cambridge, MA 02142