Wyrick, John
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Research Interests
Cells respond to environmental or developmental signals by reprogramming the expression of specific genes throughout their genome. We wish to understand the mechanisms by which this occurs. To do so, we have used genomics-based approaches to decipher how gene expression is regulated in the model eukaryote, S. cerevisiae, with the hope that the lessons we learn in yeast will be applicable in mammalian systems.

Histone Modifications and Gene Expression

The packaging of DNA with histones into nucleosomes and higher-order chromatin structures has profound effects on transcription initiation. The chromatin structure at promoters is dynamically organized in vivo by a cadre of chromatin-modifying enzymes. One well-studied category of chromatin-modifying enzymes is histone acetyltransferases, which act to covalently link an acetyl group to lysine residues located in the N-terminal tails of histone proteins. We have used DNA microarrays to profile the changes in global mRNA levels in yeast cells missing the histone acetyltransferase Gcn5. Surprisingly, Gcn5 appears to activate transcription at some genes, but repress transcription at others. How can the same enzymatic modification have opposite transcriptional outcomes at different genes? We believe that it is the pattern of histone modifications at a promoter that dictates the transcriptional outcome. To test this hypothesis, we plan to systematically mutate lysine residues in histones, both singly, and in groups, and profile the genome expression changes due to these mutations. In doing so, we hope to decipher how the histone-modification code regulates gene expression in eukaryotic cells.

Histone Modifications and Protein-DNA interactions

The chromatin structure at a promoter is thought to modulate a gene's transcription initiation frequency by regulating the access of transcription factor proteins to their potential DNA binding sites. Covalent histone modifications, such as acetylation, are thought to play an important role in marking which promoters are accessible to transcription factors, and which are not. To test this hypothesis, we will use promoter DNA microarrays to identify all of the genomic binding sites of a transcription factor, e.g. Gal4, in the set of histone lysine mutants discussed above and in wild type yeast. This project should yield insight into how histone modifications regulate protein-DNA interactions, and could be extended to study how protein-DNA interactions are regulated during the process of DNA replication and repair.

Developing Bioinformatic Tools to Analyze Gene Expression Data

To support this work, we are building a web-accessible Relational Database to store and analyze DNA microarray data generated in our and other labs. This tool will facilitate analysis of individual microarray experiments as well as allowing users to mine the data for new insights and hypotheses in how gene expression is regulated in eukaryotic cells.

Publications

Wyrick, J.J. and Young, R.A. (2002) Deciphering Gene Expression Regulatory Networks. Curr Opin Genet Dev 12:130-136.

Wyrick, J.J. Aparicio, J.G., Chen, T., Barnett, J.D., Jennings, E.G., Young, R.A., Bell, S.P., and Aparicio, O.M. (2001) Genome-wide Distribution of ORC and MCM proteins in S. cerevisiae: High-Resolution Mapping of Replication Origins. Science 294: 2357-2360.

Simon I., Barnett, J., Hannett, N., Harbison, C.T., Rinaldi, N.J., Volkert, T.L., Wyrick, J.J., Zeitlinger, J., Gifford, D.K., Jaakkola, T.S., and Young, R.A. (2001) Serial Regulation of Transcriptional Regulators in the Yeast Cell Cycle. Cell 106: 697-708.

Ren, B.*, Robert, F.*, Wyrick, J.J.*, Aparicio, O., Jennings, E.J., Simon, I., Zeitlinger, J., Schreiber, J., Hannett, N., Kanin, E., Volkert, T.L., Wilson, C.J., Bell, S.P., and Young, R.A. (2000) Genome-wide Location and Function of DNA-binding Proteins. Science 290: 2306-2309.
*Authors made equal contributions.

Wyrick, J.J., Holstege, F.C.P., Jennings, E.G., Causton, H.C., Shore, D., Grunstein, M., Lander, E.S., Young, R.A., (1999) Chromosomal Landscape of Nucleosome-dependent Gene Expression and Silencing in Yeast. Nature 402:418-421.