|
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 Click
here for a complete list of publications.
top |