Research


GENOME-WIDE APPROACHES TO THE STUDY OF BIOLOGICAL SYSTEMS

The complexities of biological systems can now be studied with genome-wide approaches that take a global view of the underlaying biology. Biological systems can take multiple forms that range from the molecular mechanisms that function in a cell, to the regulatory networks controlling gene expression and the complex interactions that occur in whole tissue such as skin. Improper regulation and/or perturbation of the mechanisms controlling these complex systems are characteristic of many disease states. Ultimately I am interested in the regulatory mechanisms governing gene expression and in the cell biology of the human cell division cycle and the systemic autoimmune disease, scleroderma. My laboratory will pursue functional studies of novel genes identified in our genome-wide analyses in order to better understand the cell biology of these systems; antibodies have been raised against >70 novel cell cycle-regulated genes and will form the basis of initial studies.

DNA microarrays measure genome-wide patterns of gene expression (Figure 1) and provide a window into complex biological systems without requiring the researcher to make prior assumptions about the underlying biology. Genome-wide investigations allow observation of the underlying gene expression programs, which generates new hypotheses that can be investigated by more traditional methods

Scleroderma is a complex, heterogeneous and sometimes fatal disease that affects approximately 150,000 people in the US. Although scleroderma pathogenesis is poorly understood, disease progression is known to involve the immune system, the vasculature and extracellular matrix deposition. The disease has no definitive markers or curative treatments. A major component of my lab is to understand the molecular basis of scleroderma by analyzing the gene expression profiles from patients with the disease. In collaboration with Dr. Kari Connolly in the UCSF Department of Dermatology, we have created a gene expression map of skin from scleroderma patients and compared those to gene expression in normal individuals (Figure 2; Whitfield et al. 2003). The scleroderma molecular profiling project is ongoing in my laboratory and is a collaboration among basic scientist, clinicians and computational biologist

Concurrent with our studies of human disease, my laboratory is studying the regulatory mechanisms that control global gene expression using the human cell division cycle as a model. We have identified a large fraction of the genes in the human genome that are periodically expressed during the human cell cycle (Whitfield et al. 2002, Figure 3). We are using experimental and computational approaches to understand the different regulatory mechanisms that contribute to periodic gene expression in this basic process. Current work is focused on how cell cycle gene expression varies in different cell types (fibroblast, endothelial cells, etc) and the regulatory networks that control their gene expression. Ultimately, I am interested not only in regulatory mechanisms governing gene expression but also in cell biological aspects of cell division.

Whitfield Laboratory
Dartmouth Medical School
Department of Genetics
Remsen 705
Hanover, NH 03755
Phone: 603-650-1105
Fax: 603-650-1188

Home - Research - Tour the Lab - Lab Personnel - Publications - Links - Contact