Academic Background

Chromatin Structure and Regulation of Gene Expression, Cell Cycle, Cell Differentiation, and Oncogenesis

The main focus of our research is to understand how factors that regulate the opening and closing of chromatin structure affect a diverse set of biological processes, including gene expression, cell cycle progression, initiation of cellular differentiation, tumorigenesis, and mouse development.  Most of our work focuses on the mammalian SWI/SNF complexes, which are multi-subunit, ATP-dependent enzymes that alter chromatin structure.  These evolutionarily conserved enzymes physically alter the structure of chromatin to regulate gene expression.  Surprisingly, component subunits of these enzymes can interact with known tumor suppressors to regulate cell growth and also can act as tumor suppressors themselves.  Some subunits are required for embryogenesis.  Additionally, SWI/SNF proteins can be targeted by viral regulatory proteins upon infection of cells by diverse viruses such as HIV, HPV and EBV.

Our past research efforts have reported isolation of human SWI/SNF complexes and functional characterization of their ability to alter in vitro assembled chromatin templates and promote transcription factor interactions with the template.  Work on the mechanism of SWI/SNF mediated chromatin remodeling is ongoing in the lab, with specific interest in how post-translational histone modifications affect chromatin remodeling.  To address biological function of these enzymes, we created cell lines that inducibly express mutant forms of the enzymes and are utilizing them to examine the role of these enzymes in numerous gene activation and cellular differentiation events.  In particular, we have observed that expression of the mutant SWI/SNF chromatin remodeling enzymes prevents muscle and adipose differentiation.  Detailed examination of the temporal interplay between tissue specific regulatory factors and diverse chromatin remodeling enzymes is in progress (see figure).  To date, we have identified disparate functions for SWI/SNF enzymes at different promoters, including facilitation of pol II pre-initiation complex function and facilitation of activator binding to the promoter.

In addition, we are continuing our efforts to assess the function of the SWI/SNF subunit termed Ini1.  Ini1 is missing or mutated in a number of pediatric rhabdoid and other tumors, suggesting it acts as a tumor suppressor.  In collaboration with Steve Jones’ lab, we previously showed that approximately 15% of mice heterozygous for Ini1 exhibit tumors, predominantly in the head and neck region, demonstrating that Ini1 does act as a tumor suppressor.  Ini1 null embryos die around the time of implantation in the womb, indicating that Ini1 is essential for normal mouse development.  However, analysis of SWI/SNF function in Ini1 deficient cells derived from patient tumors shows that multiple SWI/SNF functions are unaffected by the absence of Ini1.  Further analyses of ini1 function and the regulation of Ini1 expression are in progress.

Figure

Temporal order of events during activation of the PPARgamma gene during adipogenesis
(see Salma et al, MCB 24:4641, 2004)

Laboratory Personnel

Current Personnel

Previous Trainees