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William Greenleaf: The DNA Folding Question

William Greenleaf: The DNA Folding Question
Assistant professor, Stanford University School of Medicine
Recommended by Michael Snyder, Stanford University

Greenleaf.jpgEach cell in the human body contains some two meters of DNA, but that length is folded and folded again to fit into a nucleus that is only five microns large.

"That's a spectacular topological challenge for the cell," said William Greenleaf. He added that nearly all — about 97 percent or 98 percent — of the DNA in a cell is folded and stored away and not accessible to the transcription machinery. That, he said, affects the biological state of the cell.

Only part of how that folding occurs is well understood, Greenleaf said. He noted that the structure of DNA and of the nucleosome around which it wraps is well known, but beyond that point the understanding of how DNA is packaged breaks down.

"We're trying to develop methods to get at those basic structural questions using high-throughput sequencing," he said.

In addition, his lab at Stanford is also interested in determining how DNA sequences can encode information that leads to the building of complex three-dimensional objects.

His lab there is new, and while getting it off the ground has been a challenge, Greenleaf noted that the funding situation in the US is also worrisome. "I spend a large fraction of my time, unfortunately, writing grants," he said. He added that the US National Institutes of Health is trying to accommodate and take the specific challenges of young investigators — such as not having a long publication record — into consideration.

Paper of note

As a graduate student, Greenleaf, along with his colleague Matthew Larson, studied how RNA polymerase terminates transcription. As they wrote in Cell in 2008, termination of transcription occurs when the RNA polymerase reaches a sequence encoding a CG-rich hairpin followed by a slippery U-rich tract. At that point, Greenleaf said, the transcript is essentially yanked out of the polymerase.

And this past October, Greenleaf and his colleagues published a report in Nature Methods detailing how they were able to perform open chromatin assays on clinical samples and within a clinical timescale. Their approach, called ATAC-seq for assay for transposase-accessible chromatin using sequencing, allows researchers to examine nucelosome position, transcription factor binding, and chromatin accessibility at the same time.

Looking ahead

Building on that Nature Methods paper, Greenleaf said that in the next few years, epigenomics and the regulome would become more important in the clinic as part of the push toward personalized medicine.

"That's one of the reasons that we're excited about what we are working on," he added. "I think that that is one place where the field needs to go is into human beings and clinical samples and disease."

And the Nobel goes to…

While Greenleaf doesn't think that he'll win a Nobel Prize, he said that pursuing a better understanding of how DNA folds and is stored and the effect of that on biology is an interesting avenue to pursue.

"Our understanding at the length of kilobases is poorly characterized, I'd argue and it's probably biologically important and interesting," he said.

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