Robert E. Kingston
To maintain the differentiated tissues in any organism, cell-type specific genes must remain ‘on' for the lifetime of the organism in one cell type, and ‘off' for the lifetime of the organism in other cells. Thus the same gene, with the same primary DNA sequence, can be kept heritably ‘on' across numerous cell divisions in one cell and be kept heritably ‘off' across numerous cell divisions in a nearby cell. This differential heritable regulation of the same gene, frequently referred to as epigenetic regulation, occurs at least in part by maintaining different states of the chromatin over a gene when it is on as compared to when it is off. When a gene is maintained in an off state, the chromatin packaging is maintained in a state that inhibits transcription factor function, and thus blocks transcription of the gene. When a gene is maintained in an on state, the chromatin is maintained in a configuration that is permissive for transcription.
Our laboratory studies the protein complexes that accomplish this epigenetic regulation using a combination of biochemical and in vivo approaches. The nucleosome is the fundamental building block of chromatin, and genetic studies imply that altering nucleosome structure plays a central role in epigenetic regulation. We characterize the regulation of nucleosome structure by ATP-dependent remodeling complexes and by complexes in the Polycomb-group (PcG). ATP-dependent remodeling complexes open nucleosome structure to create access and tend to be involved in maintaining ‘on' states. PcG complexes can methylate DNA and can create a compacted chromatin structure we believe is critical to maintaining an ‘off' state. We examine the structures that are formed by these complexes using biochemical and crystallographic techniques and we examine the structure of target genes of these complexes in ES cells and somatic cells using high throughput technologies to assess large scale changes in chromatin structure.
Richard B. Simches Research Center
185 Cambridge Street, CPZN 7250
Boston, MA 02114