How is it inherited

A conundrum in the heterochromatin field is how domains that initially spread to variable sizes are then intergenerationally maintained at high fidelity. On the one hand, heterochromatin expansion has to be dynamic and reach to the size appropriate for a given cell fate, for example, by spreading from nucleation sites in a stem cell with generally open chromatin. However, after regulator genes coding for of alternative cell fates are first engulfed by heterochromatin, their stable repression is essential to cell fate maintenance. This is because master regulators even when expressed transiently could kick off alternative transcription programs. We address this area on two levels:

1. To understand the relationship between initial spreading into previously active chromatin and maintenance, we use single cell fission yeast system to study the real-time dynamics of the heterochromatin spreading reaction in relation to the cell cycle. We are leveraging the concept of hysteresis to define which chromatin loci possess the capacity for memory formation and assess the genetic requirements for memory.

2. To understand the developmental fate of heterochromatin regions and pathways ensuring their stable maintenance, we examine murine lineage trajectories involving the G9a and GLP heterochromatin pathway. We focus on hematopoietic differentiation and as well the early transitions in embryonic stem cells. Finally, we are curious to understand how heterochromatic memory has evolved. To address this question, we

3. Are sampling the diversity if H3K9 methylation “writers” and “readers” to understand the parameter space of stable vs. unstable domains, size, and degree of repression that can be generated.