Abstract #53

Using natural variation to uncover post-transcriptional regulatory mechanisms. Aimée Dudley^1,3, Suin Lee^2,3, Dana Pe'er¹, Anupriya Dutta¹, George Church¹, Daphne Koller². 1) Department of Genetics, Harvard Medical School, Boston, MA; 2) Computer Science Department, Stanford University, Stanford, CA; 3) equal contributions.
   Variation in DNA sequence has a major impact on an individual’s response to environmental insults, disease, and therapies. We have developed a computational method, called Geronemo (genetic regulatory network of modules), that aims to decipher both the cell’s regulatory network and perturbations to it resulting from sequence variability. Given gene expression data from different individuals, the algorithm automatically constructs a set of regulatory modules - sets of co-regulated “target” genes and predicted regulators. We piloted this method using a publicly available yeast gene expression dataset that examines natural variation of over 100 individuals (Brem & Kruglyak (2005) PNAS 102:1572). Overall, our model captured regulatory relationships spanning a wide range of mechanisms, including transcription factors, signaling molecules, chromatin modification factors, RNA processing/ stability, and protein translation.
One interesting module contains a set of ~140 co-expressed target genes that have mitochondrial functions. These genes are highly enriched for mRNA transcripts whose 3’ UTRs are bound by the RNA stability factor Puf3. The top predicted regulator in this module is Dhh1, a component of yeast P-bodies. P-bodies are dynamic RNA-protein complexes in the cytoplasm that are the site of RNA degradation and translational repression. Our computational predictions and experimental validation suggest connections between a sequence-specific RNA binding protein (Puf3), specific RNA transcripts, and P-bodies. Taken together with results from a published genetic screen (Irwin, et al. (2006) Genome Res 15:641), our work suggests the existence of a common pathway for post-transcriptional gene regulation, including P-body components, translation factors, and genes of unknown function.

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