Genomics Scale analyses:
We have collaborated in a range of studies using genomic tiling
arrays to map sites of transcription factor binding, intergenic
transcripts, genomic structure variation, sites of early and late DNA
replication, and chromatin structure
mRNA expression patterns in the hematopoietic/immune system. We have
analyzed patterns of mRNA expression in purified cell types in the
immune and hematopoietic system, and are characterizing at a genomic
level transcription factor binding sites and chromatin structure in
these cells.. One area of focus is the differentiation and response
patterns of neutrophils and monocytes to various stimuli.
studies are planned for dendritic cells and various subsets of
Genome wide mutation or polymorphism detection. We have developed
approaches for efficiently separating DNA fragments containing internal
mismatches from perfectly matched fragments and are working on methods
for applying this at an entire genome level to rapidly detect somatic
mutations in neoplasias, as well as newly arising mutations in
experimental systems or man.
In collaboration with Professor M. Snyder
and the Yale Center for Genomics, we are working on approaches to
detect at an unprecedented level of sensitivity, speed, and accuracy,
deletions and perhaps even inversions across the genome.
Protein expression patterns.
We have using 2d PAGE and mass
spectrophotometric identification of proteins to investigate changes in
protein patterns in hematopoietic cells and correlate these with mRNA
changes. In particular we will be investigating the complement of
transcription factors in these cell types and their modifications,
using approaches that can give us relative information about these on a
very broad scale.
We are studying two genes in the major hjistocompatibility complex
that may represent additional roles for the complex in the function of
the immune system. One gene is strongly expressed in dendritic cells
and induces a number of cell types to from long (cytonemes-like)
filopodia, so that it may be involved in the formation of dendritic
cell morphology. The other gene is ubiquitin analogue with some
differences, and is also selectively expressed in certain cells of the
immune system and may be involved in regulating cell response to
We are investigating the role of certain globin gene upstream
sequences and a particular members of the SWI/SNF family of genes in
regulating globin gene switching and response to enhancers, and are
characterizing previously undescribed multi-protein complexes that bind
to globin regulatory regions.
Studies are continuing on WRN, a helicase that is mutated in Werner
disease, a Mendelian disorder that mimics premature aging in man. We
are interested in the types of DNA structures that WRN may interact
with in vivo, the proteins that associate with WRN, and the possibility
that the role for WRN in resistance to oxidative damage is responsible
for the aging-like phenotype seen in Werner patients.