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Sheng Zhong: Comparing Gene Regulatory Networks Across Species

Sheng Zhong, assistant professor of bioengineering and a faculty member in the Regenerative Biology and Tissue Engineering Research Theme, has just received the 2010 NIH Director’s New Innovator award, a prestigious recognition that is intended to “stimulate innovative research and support promising new investigators.” The grant supports young investigators with funds up to $300,000 in direct costs per year for five years.

Zhong uses systems biology approaches to study cellular differentiation and evolution. One thing Zhong looks at is how gene regulatory networks (GRNs) orchestrate the level of expression of each gene by controlling whether, when and how vigorously that gene will produce RNAs and proteins. But to study GRNs, one needs not just DNA data, but RNAs, proteins, and biochemical modifications and a way to study them all together, hence systems biology.

Zhong’s group pioneered looking at the GRNs of embryos before they are implanted in the uterine wall. Recently, Zhong and his group have observed that close to forty percent of the genes shared by humans, mice and cows are expressed differently pre-implantation. This is far more variation at such an early developmental stage than generally assumed. The group’s findings were published as a cover article in Genome Research and featured in Nature.

“The traditional thought was that different mammals would develop in a similar way at least until implantation,” says Zhong. “The shapes of the embryos under the microscope, the number of cells, and the morphology of cells, were extremely similar. So that guided the conventional understanding.”

Zhong and his collaborators were also able to determine the mechanism for the variation of the GRNs.

“That initial finding was a surprise,” says Zhong. “And then from that observation we started to investigate what are the genomic reasons that could essentially give rise to such a large variety of gene activity. This turned out to be a pleasant surprise that we could work out a part of the mechanism.”

In short, Zhong’s group, and collaborators from Massachusetts General Hospital and the Genome Institute of Singapore, demonstrated that transposable elements, aka “jumping genes,” might be capable of re-wiring the gene regulatory network. Altered gene regulation can also be introduced in some other cases by point mutations that affected the binding of regulatory proteins to DNA, notes Zhong.

These experiments suggest a method by which evolution could occur; Zhong’s group did find “traces of evolutionary changes of GRN structures, also termed re-wiring of GRNs. “

He is particularly excited about these preliminary findings for their potential to help us understand how evolution shapes the human genome. In the near future, Zhong hopes to use the analysis of pluripotent stem cells and pre-implantation embryonic development as “testbed questions” to build and test quantitative evolutionary models for GRNs. Although an enormous amount of research into DNA as it relates to evolution has been undertaken, other substrates, such as RNA and proteins have been much less studied with regard to what elements are conserved or changed during evolution. This is something Zhong has focused on.

“We wanted to put proteins, RNAs and genomes and the interactions among them in one context to study evolution,” says Zhong. “We hope to use this empirical study together with theoretical developments to be able to understand evolution from a slightly more comprehensive matter and hopefully reach some principled understanding of how evolution is working.”

Zhong’s ultimate goal is to systematically understand and appreciate the differences in a wide range of mammalian GRNs.  He is in the process of adding pig and opossum, thanks to the expertise of campus experts. Ideally this work will help the scientific and medical communities understand how findings from other animals can be extrapolated to human biology and to what extent those findings may need to be adjusted.

His findings also suggest that multiple gene regulatory networks can guide early embryonic development, says Zhong, who hopes that information can be harnessed to make pluripotent cells from adults cells more quickly, efficiently and inexpensively.