Probing heterochromatin growth and memory dynamics in live single cells

Each cell of an organism contains the same genetic information, yet development of unique cell types requires that only part of this information be accessible in any given cell. This selective access is governed by structures inside the cell nucleus that assemble along large stretches of a chromosome, grow to variable extents depending on the cell type and then repress the underlying information.

If this process is repeated every cell division, this repression is heritable. It remains unclear how these structures, known as heterochromatin, (i) grow along the chromosome, and (ii) “remember” their sites of assembly and growth over cell divisions. This research project aims to resolve these questions, and thereby help lay the foundation to build or manipulate genetic information-controlling heterochromatin structures to drive cells to adopt new fates and perform new functions.

The project will also educate diverse undergraduate and graduate students in different scientific fields, including genetics, biophysics, cell biology, and biotechnology, through research training and teaching opportunities.

While the genetic requirements for gene silencing by heterochromatin have been long studied, the rules governing heterochromatin growth (spreading) along the chromosome in cells remain opaque. Neither it is understood why certain heterochromatin elements epigenetically maintain themselves across cell divisions while others do not. In this project, the single-celled fission yeast model system is employed to investigate the mechanisms of spreading and maintenance of heterochromatin.

The research will combine the ability to visualize and quantify spreading in real-time in single fission yeast cells with Langevin dynamics modeling to distinguish different models of how heterochromatin spreads along the chromosome within the cell cycle. To understand how heterochromatin formed by spreading is remembered across cell divisions, hysteresis measurements with fission yeast cells containing heterochromatin spreading reporters will be used to assess the degree of memory within a given heterochromatin domain.

The power of yeast genetics, single cell imaging and modeling combined is expected to yield new insights into the molecular origins of epigenetic memory.

This research is funded by the Genetic Mechanisms program in the Division of Molecular and Cellular Biosciences in the Directorate of Biological Sciences.

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.