My lab is interested in understanding the molecular basis of essential processes that regulate gene expression. We use biophysical, biochemical methods, and structural methods, including X-ray crystallograph. Our insights into these fundamental mechanisms will contribute to a better understanding and ability to regulate gene expression processes involved in human diseases from cancer and heart disease to bacterial infections and will assist in drug development efforts.
Our studies focus on the following questions:
- How is chromatin structure modulated for DNA-dependent processes?
- How do transcription factors and pioneering factors activate gene expression?
- How are genes coordinately regulated by quorum sensing in bacterial pathogens?
Modulation of chromatin structure
The eukaryotic genome is packaged by histones into nucleosomes that together with non-histone proteins form higher order structures known as chromatin. This chromatin structure must be dismantled for factors that carry out the processes of transcription, replication, DNA repair, and recombination to gain access to the DNA. Numerous protein-DNA interactions, protein-protein interactions, and covalent modifications actively regulate DNA accessibility, but the molecular mechanisms by which this dynamic remodeling of chromatin occurs are still not well understood. Therefore, we will need to understand chromatin assembly, disassembly, nucleosome remodeling and accessibility, and gene regulatory processes at the molecular level in order to achieve the ultimate goal of being able to modulate the activity of genes at will.
Nucleosome dynamics play an important role in activated gene expression. We are studying the histone chaperone Asf1, because of its central role in chromatin dynamics. Asf1 binds to a dimer of histones H3 and H4, carrying the histones for post-translational modifications and hand-off to other histone chaperones in the cell. Chromatin assembly and disassembly systems are essential and fundamental to all DNA-dependent cellular functions, and are also important in human cancer and aging processes.
Nucleosome dynamics. A nucleosome assembly funnel illustrates the energetics of nucleosome assemby and shows Asf1 chaperoning histones H3/H4.