Grant: Operating Grant

If you wanted to understand an electronic device like an iPhone, you would likely look at the individual electronic components, see how they are wired together and then figure out how individual and groups of components dynamically respond to inputs and what signals come out as a result. You'd start with individual components and then look at hierarchically more complex two, three or more component relationships. Along the way, you'd make lists of motifs, groups of different components that behave the same way, to try to figure out the modular organization of the whole. Can the same logic be applied to life? The Nobel laureate Sir Paul Nurse recently argued that we can do just this. But it is an arduous task and some aspects of regulatory organization, such as structure and dynamics, are not easy to study. We have developed novel experimental strategies that allow us to study, en masse, the structure and dynamics of regulatory circuits in cells and to dissect the relationships between individual components. The central aim of our proposal is to build on evidence for the organizing principles of chromosome structure, the DNA fibers that encode genes, to understand how the DNA is organized and modified by proteins in order that genes can be turned on or off and that the faithful replication of our DNA is achieved. We will perform our studies in baker's yeast, which has the advantage that they are simpler, but share many genes with humans including those that are most primordial and become dysfunctional with age and in diseases such as cancers. The results of our efforts will help us to more generally define how cell regulation is most vulnerable to dysfunction and what kinds of strategies could re-stabilize them. We will create new opportunities for researchers to address the most fundamental questions of life including how genes are constrained by how they are organized and whether structural constraints affect gene function and genome evolution.