NSF Award
0078940
Berger, S. L.<br/>An important new area in research on gene and genome regulation has emerged in the last decade: the direct role of alterations in chromatin structure and function in the regulation of genetic processes. In particular, it has become evident that enzymes that directly acetylate nucleosomal histones correspond to previously known transcription cofactors. These histone acetyltransferases (HATs) are often components of large protein complexes, whose function and regulation is not yet well understood. A great deal has been learned in recent years about the structure, organization and function of the Gcn5 family macromolecular complexes that acetylate nucleosomal histones and function to promote transcriptional activation. In contrast, very little is known about the complexes that possess members of the MYST family of acetyltransferases. The only complex yet identified is NuA4 from yeast, which is comprised of Esa1, an essential gene (and only essential HAT in yeast) required for cell cycle progression. Because it is essential, and involved in cell cycle progression, its mechanism of action in vivo is of significant interest, and is currently unknown. Preliminary evidence from this laboratory supports a role in repression, as well of activation, of Esa1 in vivo. The project's hypothesis is that the subunit composition of Esa1 dictates its function in repression or activation through specific targeting. Using a combination of genetic and biochemical approaches, the role of Esa1/NuA4 in vivo and how its activity is directed to specific substrates and genes will be studied in vivo. Results from these experiments will provide new insights into the role of HATs and of acetylation in vivo, and the mechanisms that confer specific function.<br/><br/>The question of how gene expression is regulated in the context of living cells is fundamental, and underlies the basis for how cells adapt to their environments. In particular, genes are present within intricate and extensive chromosomal structures that include special proteins (called histones) that permit the packaging of DNA into the tiny nuclear space. This packaging typically inhibits gene activity, and thus certain enzymes exist to alter the packaging. The research will focus on one member of a new family of enzymes that has the ability to chemically alter the histones and ultimately to regulate gene expression.
