Uncovering a Genome's Regulatory Circuitry

For this article, Jennifer Fisher Wilson interviewed Richard A. Young, professor of biology at the Whitehead Institute for Biomedical Research, Massachusetts Institute of Technology, in Cambridge, Mass. Data from the Web of Science (ISI, Philadelphia) show that Hot Papers are cited 50 to 100 times more often than the average paper of the same type and age. F.C. Holstege, E.G. Jennings, J.J. Wyrick, T.I. Lee, C.J. Hengartner, M.R. Green, T.R. Golub, E.S. Lander, and R.A. Young RA. "Dissecting the regulatory circuitry of a eukaryotic genome," Cell, 95:717-28, Nov. 25, 1998. (Cited in about 185 papers since publication) Over the past decade, scientists have learned much about the genome's transcription apparatus and about its regulation, but little about genome-wide expression circuitry. Uncovering this circuitry is fundamental to understanding living processes. Cells must adjust genome expression to accommodate changes in their environment and in their programs of growth control and development, and how coordinate remodeling of genome expression is accomplished for signal transduction pathways or for the cell cycle clock has not been determined. The functions of just a few of the components of the transcriptional machinery are understood, and only then with respect to a small set of genes. Genome regulatory circuitry research advanced significantly, however, when a group of researchers at the Whitehead Institute for Biomedical Research used microarray technology to explore how genome expression depends on various components of the transcription apparatus. The work, published in this paper, described the mRNA population of yeast cells, and revealed various insights into genome-wide regulatory circuitry of eukaryotic cells. The paper was significant for a number of reasons, but most notably because of what it revealed about RNA polymerase II holoenzyme, said Richard A. Young, lead investigator and professor of biology at the Whitehead Institute. "We found that RNA polymerase II and a few other components of the RNA polymerase II holoenzyme have global roles in transcription, but many components of the holoenzyme have roles at specific subsets of genes," Young said. "We also learned that coordinate expression of genes can be obtained by altering the composition of the holoenzyme." Using high-density oligonucleiotide array technology, Young and his research group found a high level of regulation superimposed on RNA polymerase II holoenzymes due to gene-specific transcription factors and a novel mechanism for coordinate regulation of specific sets of genes. The results also suggested that RNA polymerase II holoenzymes are responsible for initiation of transcription of all class II genes. The work expanded on the known fact that transcriptional control in eukaryotes is due in large part to the combinatorial action of promoter-specific activators at enhancers and promoters: It revealed that the general transcription factors add an additional level of combinatorial control of eukaryotic gene expression. Richard A. Young The paper also established standards for comparing selected mutants with their wild-type counterparts, Young said. "The targets of certain signal transduction pathways can be identified by comparing genome expression signatures from these experiments with signatures that modify the cellular environment," he said. Young first began studying regulation of gene expression by using a combination of genetic and biochemical approaches to identify the complete transcription initiation apparatus in eukaryotic cells. Identifying the RNA polymerase II holoenzyme led Young and his group to study the regulatory circuitry of the eukaryotic genome to understand how the apparatus is used to regulate expression of entire genomes, he said. Currently, Young and his associates are attempting to dissect the regulatory circuitry of living cells. "The metabolic pathways that were identified in the last century have proven to be important for experimental design and interpretation, and have been fundamental for drug development," Young said. "Cells have transcriptional regulatory pathways, and knowledge of these should be as important as metabolic pathways, but transcriptional regulatory pathways have yet to be identified."

Uncovering a Genome's Regulatory Circuitry

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