Research Focus

Using High-throughput Data to Understand and Modify Biological Systems

We are developing new computational and experimental approaches to understanding how transcription, signaling and metabolism change during development, in disease and in response to environmental change. 

High-throughput technologies including expression microarrays, genome-wide chromatin immunoprecipitation, proteomics and metabolomics are providing increasingly detailed views of the state of molecules in vivo.  Our goal is to synthesize these data to create a systems level understanding of cellular processes.

Transcriptional Control

The Fraenkel lab has generated the first genome-wide map of the transcriptional regulatory sites in a eukaryotic genome.  Although protein coding regions can be identified with high confidence in genomic sequences, the regions that control transcription are much harder to detect.  Transcriptional regulatory proteins bind to short, often degenerate sequence patterns and activate or repress nearby genes.  To identify these regulatory sites throughout the genome of Saccharomyces cerevisiae, we have developed new computational methods for analyzing genome-wide chromatin immunoprecipitation data and for combining these data with evolutionary data derived from related yeast species.

As we continue to work on yeast and expand our efforts into mammalian systems, we are developing new algorithms for identifying and interpreting regulatory sites.  These include:

1.      Identifying sequence motifs in co-regulated genes using evolutionary information.

2.      Discovering the proteins that bind these sequence motifs using structural, biochemical and genomic data.

3.      Decoding the function of the multi-protein regulatory sites (combinatorial control).

Combining experimental and computational methods, we are revealing how transcription is regulated in mammalian cells during differentiation and in response to treatment with pharmaceutical agents.

Disease

We are creating systems biology methods to identify potential therapeutic targets.  Our approach integrates data from a variety of sources including high-throughput genetic interaction screens and transcriptional profiling to uncover pathways that are altered in disease.  Currently, we are collaborating with members of the Lindquist Lab to analyze the causes of neurodegenerative diseases.  We are exploring the mechanisms of toxicity of alpha-synuclein and huntingtin, proteins which cause Parkinson’s and Huntington’s diseases, respectively.  We seek to discover the pathways that are altered by these proteins at early stages of disease, when pharmaceutical intervention could potentially prevent neurodegeneration.

Publications

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