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Discovery Through Computational Biology

By Bono Sen
May 2010

Martha Bulyk, Ph.D. at the podium
Bulyk gave several examples of the scope of the task involved. In the 1,200 mouse TFs that they analyzed, for example, Bulyk said her group was able to identify DNA binding domains for over 400 mouse TFs. (Photo courtesy of Steve McCaw)

Mike Resnick, Ph.D., in the foreground
NIEHS Chromosomal Stability Group head Mike Resnick, Ph.D., foreground, was one of several LMG principal investigators who joined their trainees for Bulyk's talk. LMG Postdoctoral Fellow Kin Chan, Ph.D., left, seemed to ponder the implications of Bulyk's discoveries. (Photo courtesy of Steve McCaw)

Matthew Longley, Ph.D., center
NIEHS Staff Scientist Matthew Longley, Ph.D., center, sat with other members of the Mitochondrial DNA Replication Group, headed by William Copeland, Ph.D., partly visible to his right. (Photo courtesy of Steve McCaw)

host LMG Postdoctoral Fellow Brian Chorley, Ph.D. at the podium
As host, Chorley, above, introduced the guest lecturer and moderated questions after the talk. Chorley is a member of the LMG Trainee Action Committee, which selects speakers whose research parallels investigations by NIEHS trainees. (Photo courtesy of Steve McCaw)

According to Harvard University biophysicist Martha Bulyk, Ph.D., molecular genetics is poised to take a big step forward thanks to applications of computational biology and 'omics technologies to advance understanding of how a cell responds to environmental stresses, differentiates properly, and progresses normally through its life cycle.

Speaking at the most recent NIEHS Laboratory of Molecular Genetics (LMG) Fellows Invited Guest Lecture on April 12, Bulyk( Exit NIEHS discussed her group's experimental and computational approaches to determining the interactions of transcription factors (TFs) with DNA binding sites from a variety of genomes - yeast, nematode, fruit fly, mouse, and human. In her talk on "Transcription factor-DNA interactions: cis regulatory codes in genomes" hosted by LMG Postdoctoral Fellow Brian Chorley, Ph.D., Bulyk shared impressive new findings on the intricate interactions that are an integral part of the gene regulatory networks controlling critical cellular processes and responses to environmental conditions.

Surveying the regulatory landscape

"The regulatory landscape is very complex with lots of different TFs working together to bind to lots of different binding sites," Bulyk told her audience. She pointed out that in order to understand these complex interactions at the genome level, it is important to understand the DNA binding preferences and specificities of these proteins.

Along with colleagues in her lab and other collaborators, Bulyk seeks to characterize DNA sequence-specific regulation of co-expressed genes and understand the role of variants in the DNA binding sites, including variants that affect the binding affinity of a TF for its DNA site in gene regulation.

"To do this on a genome-wide scale and to better understand the effect of regulatory sequence variants or mutants on transcription, it is important to know all the different sequence-specific DNA binding proteins and their DNA binding preferences," noted Bulyk.

"Until recently, this was not doable because there was not much DNA binding data for most TFs," Bulyk explained.  "Until a year ago, even for yeast which has over 200 sequence specific TFs, DNA binding site data were available for only half the TFs.  In higher organisms, such as humans with over 2,000 TFs, only a few have been characterized for DNA binding site data."

Universal protein binding microarray (PBM) technology

To address this problem, Bulyk's team developed PBM technology to understand the binding preferences of hundreds of TFs from a variety of genomes. So that the same array could be used to study multiple genomes, Bulyk and her colleagues created a universal synthetic sequence design to provide information on the preference of the TFs to bind to every possible DNA binding site.

The multiplex format of the PBM technology is similar to the standard microarray technology. The signal intensity for the DNA sequences at each of the spots on the PBM provides information on the binding preferences of the TFs. This method also allows the identification of previously undiscovered DNA binding proteins and their DNA binding specificities. Bulyk noted that the PBM data are complementary to in vivo ChIP chromatin immunoprecipitation (ChIP)-based studies and that the PBM data can be used to interpret microarray readout of chromatin immunoprecipitation (ChIP-chip) data to distinguish direct versus indirect DNA binding targets.

While Bulyk fascinated the audience with her findings and copious data, she also reminded her listeners of the many challenges ahead. She pointed out that there is much we still don't know about the diversity and complexity of DNA recognition by TFs in a tissue-specific, condition-specific manner. Much of the work to come will likely involve the kind of systems biology cross-disciplinary discovery approach that Bulyk herself has conducted so impressively.

"This research nicely complements the work we do in LMG," Chorley said following the talk. "Dr. Bulyk's efforts in developing experimental and computational tools to examine protein-DNA interactions allow us to re-examine old ideas and datasets to uncover things that were not possible before."

(Bono Sen, Ph.D., is the science education and outreach program manager for the NIEHS journal Environmental Health Perspectives.)

A Young Investigator with a Stellar Career

Just nine years after completing her Ph.D. as a National Science Foundation fellow, Bulyk is already an associate professor of Medicine and Pathology at the Harvard University Medical School and Brigham and Women's Hospital, as well as a member of the faculty of Harvard-Massachusetts Institute of Technology (MIT) Division of Health Sciences and Technology and head of the Bulyk Lab at Harvard.

Bulyk is also an associate member of The Broad Institute of MIT and Harvard( Exit NIEHS, and an associate member of the Dana-Farber Cancer Institute's Center for Cancer Systems Biology. At an age when the average junior scientist has just received that first grant as a principal investigator, Bulyk already has nearly 50 peer-review publications to her credit.

Technology Review recognized Bulyk in 2005 by naming her to the T35 list of young innovators under the age of 35 for her discoveries about gene regulation. Each year, the publication recognizes young technologists and scientists whose inventions and research its editors find most exciting and potentially world changing.

Bulyk's research has also been recognized by the Faculty of 1000 Biology - an online research service that comprehensively and systematically highlights and reviews the most interesting papers published in the biological sciences, based on the recommendations of a faculty of more than 2,300 selected leading researchers.

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