BU chemist to map DNA's surface, uncovering details that will show how structure abets function

11/03/04

Thomas Tullius receives NIH grant for ENCODE technology-development project

(Boston) -- In a second round of funding for technology-related research that will contribute to the international research effort known as ENCODE, the National Human Genome Research Initiative (NHGRI) is supporting a Boston University-based effort to map the topography of the DNA molecule. Prof. Thomas Tullius, chairman of Boston University's Department of Chemistry, has received a three-year, $870,000 NHGRI grant to map the bumps, dips, and turns that characterize the surface of "naked" DNA.

Tullius's research will give scientists a finely detailed picture of how the most fundamental aspects of naked DNA -- DNA without proteins bound to its surface -- influence its function.

Tullius is one of six principal investigators to receive technology development grants from NHGRI, a part of the National Institutes of Health. The new grants, which total $5.5 million, represent the latest infusion of support to researchers selected for ENCODE projects. ENCODE, or encyclopedia of DNA elements, picks up the search for understanding the human genome where the Human Genome Project left off. Composed of scientists from government, industry, and academia from throughout the world, ENCODE is dedicated to producing a comprehensive catalog of elements crucial to biological function in the roughly 98 percent of the human genome that does not code for proteins.

ENCODE researchers are bringing their individual investigations to bear on a particular 1 percent of the genome selected by ENCODE coordinators at NHGRI. Tullius's research on this designated genomic neighborhood aims to decipher the patterns of its landscape and, in the process, build tools that researchers can use to map protein-binding sites.

His research has three goals: to build a database of patterns of DNA's sequence and structure found using a special probe, to develop computational methods that can predict these patterns in any sequence of DNA, and to use these experimental and computational approaches to build structural maps of the genome. To build the database, Tullius will expand earlier research efforts to determine patterns of naked DNA using a chemical probe called a hydroxyl radical. These radicals can spot a particular hydrogen atom in a deoxyribose, a component part of DNA, and can cleave the DNA molecule at that point. The pattern of these cleavages provides a picture of the surface of DNA that is accessible to the probe.

By applying this probe to the ENCODE-selected genome segment, Tullius will gather experimental data that he will use to achieve his second aim: the development of a robust, computational model for predicting cleavage patterns in any DNA sequence.

Tullius plans to then build maps of protein-binding sites and sequences critical to the folding of chromatin, the nuclear structure that condenses to form chromosomes during DNA replication. DNA bound up as chromatin has a complex structure -- it twists around histone proteins, turns upon itself, and, in general, is not an easily accessible item, especially for proteins that need to bind to it for transcription. It is known, however, that this structure is dynamic and that DNA spontaneously unwraps to allow proteins to bind. By applying both his experimental and computational techniques -- chemical probes and pattern-discerning software -- Tullius will be able to build three-dimensional structural maps of naked DNA, giving researchers a detailed idea not only of where regulatory proteins bind to genomic DNA, but also of how DNA's structure abets its function.

The six 2004 technology development grants are the second set of such grants awarded by NHGRI. Grants for the first set also resulted in funding work being done by a BU researcher. In 2003, Zhiping Weng, an assistant professor of biomedical engineering in BU's College of Engineering, received support for her work to develop or improve technologies used to determine how genetic elements, associated with what are known as promoter regions, act individually and collaboratively to regulate protein-encoding genes.

Other second-round grants went to researchers at the Genome Institute of Singapore; Intronn Inc., Gaithersburg, Md.; The Research Foundation of the State University of New York, Albany; The Salk Institute, La Jolla, Calif.; and the University of Texas, Austin.

Source: Eurekalert & others

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