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The Quest for Gene Regulatory Elements

  • Title: Assistant Professor, Duke University
  • Education: PhD, University of Michigan, 2001
  • Recommended by: Francis Collins

The identification of all gene regulatory elements throughout the entire human genome is no small feat. But such is the focus of Greg Crawford, whose research focuses on open regions of chromatin that mark all manner of regulatory elements, including promoters, enhancers, silencers, insulators, and locus control regions, known as DNase1 hyper-sensitive sites.

According to Crawford, traditional Southern blotting methods are limited to studying only small regions of the genome and are very time consuming. In order to get the bigger picture, he and his colleagues have developed a high-throughput sequencing method called DNase-sequencing and a tiled array method called DNase-chip to identify all DNase1 hypersensitive sites in the genome from multiple cell types. “We have done this method with blood cell types, T-cells, as well as human embryonic cell types,” says Crawford. “We are starting to get an idea of what is similar and what is different between these cell types, but [these techniques are] going to help us understand more about why genes are turned on and turned off in different parts of our body.”

One of the biggest hurdles in Crawford’s line of research is obtaining normal cell types. There are a lot of immortalized cell types that are easily grown and cultured, and these are great model systems to work with, he says, but he runs into problems because many of these cells have abnormal karyotypes as well as major insertions or deletions, and sometimes they having missing chromosomes. “I am really interested in applying this technology to normal cell types, but the problem is in obtaining them,” he says. “Blood cell types are quite easy because you can just isolate these different cell types from human blood, but getting other cell types is going to be much more of a challenge.”

Looking ahead

Down the road, Crawford would like to see a complete catalogue from most cell types in the human body, as well as different stages of development including undifferentiated and dif-ferentiated stem cells and cell types. He hopes that such tools would provide an improved understanding of how diseases are a result of genes being switched on or off when they normally would not be. “I also think this will be helpful for some of these major association studies that are going on trying to identify regions that are associated with some of these common diseases,” he says. “One of the problems that a lot of researchers are faced with [is] how do you find the actual causative polymorphism — especially if it’s not actually in a gene — once you narrow down a region of the genome that’s associated with the disease?”

As with many researchers, Crawford says that cheaper sequencing platforms would be a boon to his research. He would like to see a tool come along with the ability to sequence billions of reads instead of millions. In addition, he’d welcome any technology that could analyze the massive amounts of data culled from countless sequence reads as well as whole genome tiled array data.

Publications of note

A significant publication for Crawford is a proof-of-principle paper he published in PNAS entitled “Identifying gene regulatory elements by genome-wide recovery of DNase hypersensitive sites” back in 2004. The paper outlined his team’s high-throughput technique for looking at DNase1 sites as an alternative to the more time-consuming Southern blotting method. He and his colleagues successfully demonstrated that it was possible to move beyond the Southern blotting method and look at the entire genome all at once.

And the Nobel goes to …

Crawford says that if he were to win, he would like to be recognized as a team player in the quest to understand global gene regulation.