Heterochromatin dynamics during inheritance and adaptation

PROJECT ABSTRACT Retaining pre-existing histone modifications that control gene expression is essential to maintain cellular identity. Yet, cells often encounter unexpected changes to their environment that force them to rewire transcription. My overall vision is to determine how the dynamic properties of the epigenome can be tuned to ensure stable inheritance during development while enabling plasticity during adaptation. Histone H3 lysine 9 methylation (H3K9me) is essential to form transcriptionally silent heterochromatin domains, which play crucial roles in maintaining genome stability and cellular identity. This process depends on a minimal set of core factors that are conserved in organisms ranging from yeast to humans. Fission yeast (Schizosaccharomyces pombe) is an outstanding model system to develop a molecular scale understanding of how heterochromatin is established, maintained, and dynamically remodeled during stress. Despite the stable nature of heterochromatin silencing, the interactions between heterochromatin proteins and H3K9me nucleosomes, paradoxically, are highly dynamic. These observations highlight significant conceptual and methodological gaps that we will address during the next five-year period: 1) How do cells integrate transient protein binding events on the millisecond timescale to enforce stable epigenetic silencing across multiple generations? 2) How do cells exploit transient interactions to form heterochromatin at new locations in the genome during adaptation? In this proposal, we use a multi-disciplinary approach combining genetics and genomics, biochemistry, and microfluidic tools to elucidate how cells reconcile the need for stability with plasticity in establishing and maintaining heterochromatin. Uncovering these molecular architectures will enable us to envision and design new classes of chromatin states that are robust, durable, and yet flexible to change in response to external cues.