CAREER: Programming epigenetic inheritance by engineering nuclear compartmentalization

All cells in the body share the same genetic blueprint, yet they can take on specialized forms and functions, such as skin, muscle, or brain cells. This process depends on certain sets of genes being turned on or off and these patterns of expression being passed on to subsequent generations as cells divide. This project will investigate a specialized region of the genome called heterochromatin, a tightly packed form of DNA that silences gene expression.

The research will use fission yeast as a model organism to test how heterochromatin, which is formed by a protein called HP1, helps cells protect gene expression memories. Beyond advancing scientific knowledge, the project will create opportunities to enhance undergraduate and high-school education through a hands-on research program that engages students in cutting-edge science.

This effort will train the next generation of scientists, promote discovery-based learning, and share the excitement of scientific exploration with a broader audience.

This project investigates how HP1-mediated genome compartmentalization maintains epigenetic memory. HP1 proteins organize specific regions of DNA into compact, inactive structures that are refractory to transcription. Using novel genetic tools that specifically perturb distinct molecular features of the fission yeast HP1 protein, the project will pursue three objectives: (1) engineer synthetic H3K9me binding modules to directly test how compartmentalization influences epigenetic memory, (2) determine how compartmentalization buffers cells from stochastic noise, and (3) leverage evolutionary comparisons of HP1 proteins to identify critical sequence features and protein-protein interactions that facilitate epigenetic inheritance.

The project will also establish the Yeast Epigenetics Teaching Initiative (YETI), providing research opportunities for undergraduate and high school students. YETI participants will contribute directly to the research goals by helping discover new alleles of HP1 proteins that enhance epigenetic memory.

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.