MCA: Quantitative understanding of heritable epigenetic changes

Interactions with the environment in one generation of an organism can cause effects that last for many generations even without changes in DNA sequence. Being able to predict what genes will be affected in this way can enable a better understanding of hereditary diseases and suggest approaches for evaluating environmental exposures that can have lasting effects.

By focusing on how single genes respond across generations in a model nematode, this project develops predictions for heritable change that can be tested using experimental measurements while involving undergraduate and graduate students in the research. Undergraduate students learn to represent and explore ideas through simulations. Graduate students learn to think, with simulations, about how to constrain possible inferences from their experiments before publishing their work.

The enhanced quantitative reasoning imparted through the research and broader efforts prepares the upcoming workforce for an increasingly data-rich world. This award enables the PI, who is an experimentalist, to acquire expertise in modeling and theory development in biology.

This project is developing a unified theory of heritable epigenetic changes. It integrates experimental measurements with mathematical description and quantitative simulations by focusing on the changes that occur in the expression of single genes across generations in the nematode C. elegans. Since different sequence contexts prevent or promote heritable changes in RNA-mediated control of gene expression, the project measures differences in small RNAs, mRNAs, and other key regulators for six different contexts when the same coding sequence is targeted for RNA silencing.

Quantitative measurements are used to constrain simulations that predict the nature and duration of transgenerational epigenetic change. In parallel, analytical descriptions of the regulatory relationships that can promote or hinder heritable epigenetic change are pursued to achieve deeper understanding.

This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.