Regulation of Chromatin Structure and Gene Expression John Tamkun, MCD Biology The Tamkun lab investigates regulation of chromatin's high order structure and its role in gene expression. Composed of both DNA and proteins, chromatin's ability to fold enables the eukaryotic genome to be packaged into an extremely small volume of space inside the nucleus of the cell. Proper transcription and replication of the genome also depend upon the precise regulation of these dynamic structures, with defects in these processes believed to underly many human diseases, such as cancer.

Nucleosomes and other components of chromatin repress transcription by blocking the access of transcription factors and other proteins to DNA. Eukaryotic cells use two general mechanisms to regulate chromatin repression: the covalent modification of nucleosomal histones and ATP-dependent chromatin remodeling.

The site-specific acetylation, phosphorylation or methylation of histone tails alters the ability of nucleosomes to interact with structural or regulatory proteins. As a result, histone-modifying enzymes can have profound effects on chromatin structure and gene expression. Chromatin-remodeling reactions are catalyzed by large protein complexes that use the energy of ATP hydrolysis to alter the structure or positioning of nucleosomes. By modulating the access of proteins to DNA in the context of chromatin, chromatin remodeling complexes play important roles in a variety of nuclear processes, including transcriptional activation and repression; the maintenance of higher-order chromatin structure; and DNA replication, repair and recombination.

To fully understand the mechanism of action of chromatin remodeling complexes, it will be necessary to determine how their activities are regulated; how they are targeted to specific genes; and how they interact with histone-modifying enzymes and other regulatory proteins to modulate chromatin structure and transcription. Our laboratory uses the fruit fly Drosophila melanogaster as a model organism to address these important issues.

We use a combination of genetic, biochemical and molecular approaches to study Drosophila chromatin-remodeling complexes. Much of our current research is focused on their roles in transcriptional regulation and the maintenance of higher order chromatin structure. We also study the regulation of chromatin-remodeling by acetylation and other post-translational modifications of chromatin. Finally, our laboratory has a long-standing interest in the role of chromatin and chromatin remodeling complexes in cell fate specification.

Highly conserved counterparts of Drosophila chromatin remodeling factors are present in humans. Mutations in genes encoding subunits of human chromatin-remodeling complexes are associated with cancer and other diseases. Our studies of Drosophila chromatin-remodeling factors are therefore directly relevant to human health.