Inside the nucleus, DNA is packaged with histones into chromatin. Nucleosomes, which are the smallest packing units of chromatin, resemble spools of DNA that wrap around a core of histone proteins. In vitro, nucleosomes are structurally stable and are obstructive to the access of most DNA binding factors. But in cells, thanks to chromatin remodeling enzymes and histone chaperones, nucleosomes are constantly being mobilized, disassembled, and reassembled. These chromatin remodeling activities are involved in virtually all nuclear processes, such as transcription, DNA replication, and repair, and are critical for normal tissue growth and cellular differentiation. Emerging evidence has now linked mutations in the chromatin remodeling pathways to numerous human cancers .
In our laboratory, we study the underlying principles related to how cells organize chromatin structure to accommodate and control gene expression. For example, when a gene is being turned on, how does the transcription machinery assemble at the promoter in the context of chromatin? In addition, we are interested in understanding how chromatin structure is reorganized in response to DNA damage. Using the budding yeast model system and a wide array of biochemical and genomic approaches, we are currently addressing these specific questions:
1) What are the mechanisms by which chromatin remodeling enzymes alter chromatin structure in and around the promoter to facilitate the loading of the transcription machinery?
2) What are the roles of the transcription machinery in remodeling chromatin at promoters?
3) How do chromatin remodeling enzymes reorganize chromatin structure in response to DNA lesions, and what roles do they have in enabling the access of repair proteins?