Every cell in the body has the same DNA. But from those equal-opportunity beginnings, cells have to end up with vastly different casts of protein characters to perform their roles.

So it's not surprising that DNA spends quite a bit of its energy on regulating who gets to be on any given cellular stage. "A tenth of all genes are dedicated to transcription factors," Richard Myers, professor and chair of genetics at Stanford University, told BioWorld Today.

Two recent papers describe a way to learn more about transcription factors by combining chromatin immunoprecipitation or ChIP, a method to isolate regulatory proteins along with the DNA they bind, with sequencing.

"Traditionally, DNA [isolated via ChIP] has been hybridized to other chips," Myers explained. But those chips, of course, have a limited, albeit large, number of sequences on them.

ChIPSeq expands the methods by sequencing the bound DNA. Myers termed the sequencing approach, which has been enabled by technological advances in high-throughput sequencing, "more agnostic - you don't have a preconceived notion . . . You go in and see what's operating." He added that though the ChiPSeq method was not developed expressly for the purpose of mapping transcription factor binding sites, it is very well suited to it. "We've been using it like crazy," he said.

In the May 31, 2007 issue of Science, Myers and his colleagues at the California Institute of Technology and Stanford University used the method to map and sequence the binding sites of neuron-restrictive silencer factor or NRSF. They identified a number of binding sites that use previously unknown sequences to bind NRSF; the data also revealed that NRSF is a previously unknown player in pancreatic islet cell development.

And in a paper now available via advance online publication in Nature Methods, researchers from the British Columbia Cancer Science Genome Agency in Vancouver, British Columbia, and Yale University used the same principle to perform a genome-wide mapping of the transcription factor Stat1, which plays a role in regulating immunological pathways.

In the case of NRSF, Myers and his team mapped roughly 2,000 such binding sites, which is "probably on the low side" for a transcription factor, Myers said. Their agnostic method allowed them to identify atypical binding motifs. While roughly 75 percent of the sites Myers and his team found have the typical or canonical DNA sequence that binds NRSF, they also found several hundred sites that have a different sequence - most frequently, only half of the canonical motifs, which divides into two halves that are often separated by a few base pairs.

On the functional side, when the scientists investigated the functions of genes that are regulated by NRSF, synaptic transmission and development ranked very high - as did, in a bit more of a surprise, pancreatic cell development. NRSF regulated several genes, including other transcription factors that are critical for pancreatic islet cell development. Myers said that NRSF might be the initial gatekeeper in the process of beta-cell development. The results suggested that "for beta cells to develop, release from inhibition [by NRSF] has to occur," he explained.

Myers is himself a basic researcher, but thinks the implications of the ChIPSeq method go beyond basic science. "There are lots of diseases where transcription factors are dysregulated," he said, adding that even if the transcription factors turn out to be less than ideal drug targets, data on them could be "very valuable" in learning more about the pathways they activate, and parts of the drug discovery process like making animal models. "I'm not particularly product-oriented myself, but I can certainly think of lots of applications," he added.