Study sheds new light on the dark matter of genome

Vanderbilt University Medical CenterSep 19 2013

Using technology he helped develop, Vanderbilt University scientist Bryan Venters, Ph.D., has shed new light on the "dark matter" of the genome and has begun to explore a possible new approach to treating cancer.

"Clarity is everything," said Venters, assistant professor of Molecular Physiology and Biophysics who further developed the high-resolution technology as a postdoctoral fellow in the lab of Frank Pugh, Ph.D., at Pennsylvania State University before moving to Vanderbilt in January.

Venters and Pugh are co-authors of a paper published this week in the journal Nature that describes their finding.

Much of the DNA of the human genome has been called "dark matter" because only a tiny fraction, about 3 percent, makes up the approximately 20,000 protein-coding genes that are transcribed into RNA copies, and then translated into proteins.

Other parts of the genome are transcribed into non-coding RNA, presumably to perform other functions, but until recently the origin of this non-coding RNA was unknown.

Now, with a technique called ChIP-exo developed at Penn State that identifies protein-DNA interactions at near base-pair resolution, Venters and Pugh have shown that so-called transcription initiation complexes drive much of the non-coding transcription occurring throughout the genome.

In a model leukemia cell line, they discovered about 150,000 complexes along non-coding stretches of the DNA - the most ever discovered. This suggests, they concluded, that "pervasive non-coding transcription is promoter-specific, regulated, and not that much different from coding transcription (of genes)."

Venters compared the technique to the highly sensitive satellite cameras that enable web-based map applications to zoom in from a continental view to street level, "and tell house from house."

Now he is using the technique to study "the contribution that the JAK-STAT (signaling) pathway makes to the transformation and proliferation of leukemia cells - how the STAT regulatory network dovetails with other oncogenic signaling pathways."

Venters hopes this "high-resolution mapping technique" will enable him to identify - at the transcription level - the "points of convergence" between different pathways, and thus potential "vulnerability points" that could be targeted with more effective drugs than current therapies.

That's why he came to Vanderbilt, he said, because of the "collegiality" and "proximity to patients and clinicians."

"I wanted my research to be medically relevant and I wanted to make an impact in therapeutic treatments," Venters said. "To me, Vanderbilt is the perfect place to do that."