R01ES034353

High resolution epigenomic maps of yeast in response to environmental stress - gene regulation is central to all life, normal and diseased.

The long-term goal of this research project is to understand, at single base pair resolution, the molecular organization (architecture) of proteins assembled on the Saccharomyces (budding yeast) genome. Budding yeast represents an ideal model cellular system due to its simple genome, ease of genetic manipulation, and conservation of transcription and chromatin regulators with human cells.

By understanding the precise molecular architecture of epigenomes, we gain a holistic view of genome regulation mechanisms. This project will build on our published set of genome-wide Chip-Exo data that comprehensively measures the yeast epigenome consisting of over 400 distinct proteins. This expansion will involve understanding how epigenomes are reprogrammed by environmental signals.

Two broad classes of reprogramming will be examined: acute stress responses (e.g., heat shock and oxidative stress) and long-term unfolding of developmental pathways (e.g., starvation responses) brought on by chronic stress. Responses to acute stress reveal molecular architectures that pre-exist in the cell and then re-organize within a few minutes of sensing extracellular signaling. These events are typically transient and so must be captured upon reaching their temporal maxima.

In contrast, developmental pathways unfold over hours in yeast and typically rely on de novo synthesis of gene-specific transcription factors. This project will map the precise positional organization of hundreds of epigenomic components in response to heat shock and oxidative stress, and a smaller set of components in response to a much broader array of acute stresses and developmental pathways.

This project will also define the functional interdependencies of epigenomic factors, with a particular focus on the gene induction cofactors Mediator and SAGA. Relevant components of induced transcription will be rapidly depleted, then their impact on Mediator and SAGA binding to promoters examined. Other interdependencies, informed by the organization of epigenomes that will be defined during reprogramming/induction, will also be examined.

Together, these aims will help provide a more thorough understanding of the protein architecture of gene regulation that should allow computational prediction of novel gene-environment interactions in diseased tissue.

Cornell University

NOT APPLICABLE

93.113 - Environmental Health

National Institute of Environmental Health Sciences (NIEHS) [HHS - NIH]

Ithaca, New York 148536007 United States

Single Zip Code

NIH Research Project Grant (Parent R01 Clinical Trial Not Allowed) (PA-20-185)

Amendment Since initial award the total obligations have increased 376% from $687,673 to $3,273,261.