Abstract #3

A global and dynamic view of networks that regulate the transcriptional response to DNA damage. Craig Mak¹, Trey Ideker². 1) Biology, UCSD, La Jolla, CA; 2) Bioengineering, UCSD, La Jolla, CA.
   The DNA damaging agent methyl-methanesulfonate (MMS) elicits a multi-faceted response in yeast. This response includes induction of DNA repair, arrest of the cell cycle, and activation of general stress pathways. Between one tenth and one third of the yeast genome may be differentially expressed in response to DNA damage. Previously, we took a systems approach to map the transcriptional network that regulates this response. Here, we seek to identify how the interactions in this network may be temporally regulated by augmenting the existing static snapshots of the network with time-series expression data.
   Our existing network captures the regulatory interactions in a cell approximately 60 minutes after exposure to MMS. It was built by integrating MMS-induced expression profiles with genome-wide binding data for 30 damage-related transcription factors measured before and after exposure of yeast to MMS. In this work we have performed microarray experiments that measure gene expression changes at 5, 15, 30, 45, 60, 75, 90, and 120 minutes after exposure of yeast to MMS, and we have developed computational algorithms to integrate these data with our existing regulatory network. Our computational approach to data integration is based on, first, annotating genes and interactions in a network with properties derived from our time-series expression data and then, second, searching this annotated network for time-dependent patterns.
   We find transcription factors that are expressed “early” and “late” in the response to MMS. We observe that functionally distinct groups of genes are expressed at different times. Finally, we use our algorithms to identify protein complexes that may be expressed at different times and the associated transcription factors that may control their expression. Overall, this work, although preliminary, provides a global, dynamic picture of how a complex transcriptional response may be regulated.

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