CHROMATINPRINCIPLES · Principles of Chromatin Organization

Chromatin is the ensemble of genomic DNA and hundreds of structural and regulatory proteins. Together these proteins govern the gene expression program of a cell. While biochemical and genetic approaches have tought us much about interactions between individual chromatin proteins, we still lack a “big picture” of chromatin: how is the entire interaction network of chromatin proteins organized?My lab discovered that chromatin in Drosophila consists of a limited number of principal types that partition the genome into domains with distinct regulatory properties. Among these is BLACK chromatin, a novel repressive type of chromatin that covers nearly half of the fly genome. It is still largely unclear how these different chromatin types are formed, how they are targeted to specific genomic regions, and how they interact with each other.Here, I propose a combination of systematic approaches aimed to gain insight into the basic mechanisms that drive the partioning of the genome into distinct chromatin types. New genomics techniques, developed in my laboratory, will be used to construct an integrated view of the interplay of more than one hundred representative chromatin proteins with each other and with sequence elements in the genome. Specifically, we will: (1) Study the genome-wide dynamic repositioning of chromatin domains during development in relation to gene regulation; (2) Use a novel and versatile parallel genome-wide reporter assay to dissect the interplay among DNA sequences and chromatin types; (3) Combine computational modeling with a high-throughput genome-wide assay to uncover the network of interactions responsible for the formation of the principal chromatin types; (4) Dissect the molecular architecture of BLACK chromatin and its role in gene repression.The results will provide understanding of the basic principles that govern the structure and composition of chromatin, and reveal how the principal chromatin types together direct gene expression.