Our goal is to elucidate the fundamental basis of gene regulation. We study the control of transcription, the first step in the pathway of gene expression. Current work focuses on discovery of the molecular machines involved in transcription, reconstitution of the process with purified components, structure determination of the transcription machinery, and structure-function relationships in chromatin, the natural DNA template for transcription. Highlights of work from the past three years include:
1. Discovery of a human homolog of the 20-protein yeast Mediator complex. Mediator is the central processing unit of gene regulation, receiving both positive and negative inputs and transducing the information to the transcription machinery.
2. Structure determination of 10-subunit, half million Dalton RNA polymerase II, in the act of transcription, with template DNA and product RNA, by X-ray crystallography at atomic resolution.
3. Structure determination of the entire transcription initiation complex by two-dimensional protein crystallography.
4. Discovery of a stably altered nucleosome produced by a purified chromatin-remodeling complex.
Current work is directed towards the structure of the entire transcription apparatus at atomic resolution and the mechanism of transcription control in living cells.