Boston University News Release


15th December, 2003

Boston University Scientist Wins One of 14 Grants That Mark Next Phase of Human Genome Investigation

(Boston, Mass.) — Using some poetic license, you could consider the human genome as the dramatic script of each life. Its cast of star performers was recently supplied by the Human Genome Project; researchers in that effort identified each protein-encoding gene in the genome. Naming the supporting cast, however, has only just begun. This time, the playwrights will be scientists working on the National Human Genome Research Institute’s (NHGRI’s) new ENCODE project.

Among the 14 principal investigators in this leading-edge project is Zhiping Weng, an assistant professor of biomedical engineering in the College of Engineering at Boston University. Together with co-investigators Chumning Ding, research assistant professor in Boston University’s Center for Advanced Biotechnology (CAB), and Charles Cantor, a professor of biomedical engineering and director of CAB, Weng has received from NHGRI a three-year grant totaling $1.5 million.

For their study, Weng and her colleagues will work to develop new and improve existing technologies for determining the role of genetic material that does not contain instructions for proteins. Weng will concentrate on describing how particular elements, associated with what are known as promoter regions, act individually and collaboratively to regulate protein-encoding genes. By characterizing the role these elements, called cis-elements, have in transcriptional regulation, Weng and colleagues will spotlight how genetic “ensemble performances” determine everything from disease development to tissue function.

The ENCODE project is an international consortium of scientists from government, industry, and academia. ENCODE, or encyclopedia of DNA elements, picks up the search for understanding the human genome where the Human Genome Project left off. It focuses on all the biologically active elements in the roughly 98 percent of the genome that does not code for proteins, the genome’s so-called functional elements.

Although protein-coding genes are usually front-and-center in investigations of DNA, the ENCODE endeavor addresses the fact that a huge amount of the biological activity associated with the transcription of protein-encoding genes is, in fact, directed by functional elements, like the cis-elements being investigated by Weng’s team.

In a divide-and-conquer approach, ENCODE researchers will bring their individual investigations to bear on a particular 1 percent of the genome selected by ENCODE coordinators. Investigations will be divvied into two specializations: the study of large-scale existing technologies and the development of new or improved technologies for finding functional elements. Weng’s group will pursue the latter.

Weng’s team will use a battery of in-house computational algorithms to carefully characterize the starting points or “starts” of all the genes in the genome segment selected for the ENCODE project. They also will derive the promoters for these genes. Promoters, which are regions of the genome near the starts of the genes, contain high concentrations of cis-elements that are bound by regulatory proteins. These regulatory proteins can trigger or suppress gene expression and, thus, protein production.

Because many genes have multiple starts, Weng’s project will investigate the multiplicity of regulation, looking at what its effects may be on different disease conditions or on gene expression patterns in different types of cells, for example, liver cells and brain cells may be regulated to produce a particular protein but in different quantities. The team will develop algorithms that can predict how cis-elements influence the expression patterns of specific types of cells.

A novel aspect of Weng’s project is its combination of computational analysis with experimental testing. After computational analyses, Weng’s team will hone in on 40 genes for in-depth experimentation. This will include placing the genes in cells from different types of human tissue, growing those cells in the laboratory, and then, using a high-throughput, real-time technique developed by her collaborators Ding and Cantor, testing the genes to determine how the regulatory elements they carry control their expression patterns.

Cross-species comparison studies are an important, and somewhat unusual, aspect of the ENCODE project. By comparing the genomic sequences from human and other organisms, Weng will computationally identify portions of the human genome that are relatively similar to those in other organisms. These “conserved” regions are likely to harbor functional elements, since they have remained intact throughout eons of evolutionary selection. Weng will develop algorithms that incorporate cross-species comparisons in her search for regulatory elements.

“Using computational methods, it is easy to analyze a large number of genes and make predictions about the way they are regulated,” says Weng. “This project allows us to test those predictions with experiments. It also lets us collaborate with the other ENCODE laboratories, sharing our data to get the answers. This is really a project in which the whole is far greater that the sum of its parts.”

Boston University, with an enrollment of more than 29,000 in its 17 schools and colleges, is the fourth-largest independent university in the United States



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