Hinrich Boeger, MCD Biology

Eukaryotic organisms must package an enormous amount of genetic information in their chromosomes. DNA and proteins form a complex called chromatin, which enables this information to be compacted into a very small space within the nucleus. However, these chromatin structures must also be periodically unfolded in order to make genes accessible to regulatory factors and the molecular machinery that transcribes their information to make functional proteins for the cell. Hinrich Boeger's lab studies the unfolding of chromatin structures in the context of gene regulatory events. (In 2007, The Pew Charitable Trusts named Hinrich Boeger a Pew Scholar in the Biomedical Sciences).

Linking Change Associated with Promoter Chromatin Remodeling at PHO5 (Boeger et al. 2003). Topoisomer distributions of repressed (R) and activated (A) PHO5 gene circles were resolved by chloroquine-agarose gel electrophoresis (left). Centers of the Gaussian topoisomer distributions are indicated by arrow heads. refers to the shift of the distribution center upon promoter activation. equals the mean number of nucleosomes removed from the promoter (Boeger et al. 2003).

Hinrich Boeger and his colleagues are interested in the dynamics of chromatin structure and its function in the regulation of eukaryotic genes. Among the many features that distinguish eukaryotic cells from their prokaryotic relatives is the nucleosome core particle, the basic building block of chromatin structure. The core particle consists of 147 base pairs of DNA wrapped around an octamer of histone proteins very much like the thread of a spool. Nucleosome core particles form in short intervals on the DNA and contact each other, condensing the DNA of the eukaryotic cell to the confines of its nucleus.

To read out its genetic information the cell has to unwrap the packaging of its DNA at least to some extent. Indeed, the activation of eukaryotic promoters not only involves the recruitment of RNA polymerase to the promoter, as in prokaryotes, but also entails the posttranslational modification of histones and the remodeling of chromatin structure, which we observe as changes in the accessibility of promoter DNA to nucleases. The mechanisms by which these three processes interlock and the identity of the rate-limiting steps that are subject to biological control are still unclear.

The extent to which DNA must be unwrapped at the regulatory sequences of genes to allow for the initiation of transcription is still unknown. An understanding of the particular mechanisms of eukaryotic gene regulation hinges upon answers to this question. Boeger's group studies the problem in the unicellular yeast Saccharomyces cerevisiae because of the relative simplicity of its promoter structures, its amenability to genetic manipulation, and the small size of its genome, which offers many experimental advantages.

Using this experimental system, Boeger and his colleagues were able to provide evidence for the removal of promoter nucleosomes by complete disassembly of the nucleosome core particle. They have also shown that nucleosome removal is incomplete in a population of cells. Taken together, these observations suggest that a dynamic structural equilibrium between nucleosome disassembly and reassembly lies at the heart of promoter activation at some, if not all, eukaryotic promoters. On-going work in Boeger's lab is aimed at testing this hypothesis.

Remarkably, multicellular organisms have only evolved among eukaryotes. It is tempting to speculate that the particular mode of DNA packaging within the nucleus of the eukaryotic cell set the stage for the evolution of the intricate gene regulatory mechanisms that allowed for the generation of cellular diversity by differential gene expression and, thus, the profusion of pattern and form, which unfolded with the appearance of multicellular organisms approximately one billion years ago.