The biological questions we address
In the broadest terms, we seek to understand how information is encoded and dynamically utilized in living eukaryotic genomes. We focus specifically on those areas of the genome that regulate chromosomal functions such as transcription, DNA replication and repair, recombination, and chromosome segregation.
DNA is an elegant molecule, but carries its information in a language that consists of only four letters. The molecular simplicity of DNA imposes practical limits on the complexity and types of information it can encode. How do complex organisms overcome these limitations? Conceptually, information in living genomes can be visualized as existing in layers, with the information being more diffusely coded in each ascending layer. The primary layer is best represented by protein-coding DNA, which operates according to the relatively inflexible universal genetic code. A second layer encodes regulatory information through the occurrence of millions of degenerate sequence motifs potentially recognized by “sequence specific” DNA-binding proteins such as transcription factors. A third layer of sequence information is very diffusely encoded over hundreds of bases and guides the positioning and occupancy of nucleosomes, the basic units of DNA packaging. The final layer is composed of the nucleosomes themselves. Nucleosomes greatly extend the information-coding capacity of the genome by allowing overlapping, redundant, and even illegitimate information to be safely encoded in DNA sequences. Nucleosomes accomplish this by blocking regulatory protein access to most of the genome, and by dynamically allowing access to relatively small portions of the genome that are utilized specifically in a given cellular environment. We seek to characterize quantitatively how the regulation of genome accessibility occurs and how it is coordinated with the underlying layers of information encoded in DNA.
Yeast, worms, and humans: A strategy for linking basic biology and medicine
The projects in my laboratory are united by the scientific goal of understanding relationships between chromatin, transcription factor targeting, and gene expression. We use three biological systems: (1) S. cerevisiae (hereafter “yeast”) to address basic molecular mechanisms; (2) C. elegans to test the importance of those mechanisms in a simple multicellular organism; and (3) cell lines and clinical samples to directly interrogate chromatin function in human development and disease. The genomes of these organisms span three orders of magnitude in size (12 Mb, 100 Mb, and 3000 Mb respectively) and a wide range of genome complexity (~50% coding, ~25% coding, and ~1.5% coding respectively). Use of these systems, with C. elegans serving as a “stepping stone” to bridge yeast and human studies, permits us to quickly bring concepts discovered in model systems to medical relevance.
For a list of more specific research projects, please see my lab web page.
Last updated 06-22-2007