Sherman Weissman, MD

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.

Similar studies are planned for dendritic cells and various subsets of immunocytes. 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 external signaling. 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.