Determining the mechanisms underlying epigenetic inheritance of chromosome structure and gene expression states (360G-Wellcome-210645_Z_18_Z)

Gene expression states and chromosome structure can be stably perpetuated across cell division cycles in a manner that is uncoupled from direct genetic instructions. I aim to understand how chromatin can self-duplicate and be inherited. Defining the mechanisms by which chromatin components are instructive in maintaining memory is fundamental to our understanding of genome stability and cellular differentiation. In the first two aims, I focus on the mammalian centromere which is an excellent model for self-templating epigenetically-inherited chromatin, based on the histone H3 variant CENP-A. I will ask two fundamental questions: i) how can centromeric chromatin be initiated de novo? ii) how is it subsequently stably inherited? In the final aim, I will use my expertise in centromere biology to ask how heritable chromatin contributes to the mitotic transmission of active gene expression. I will employ a unique, interferon-inducible gene expression model that results in long-lasting memory of prior induction. I will discover how local chromatin structure cooperates with the transcriptional machinery to ensure robust, long-term maintenance of active transcription and determine its importance for innate immunity. Combined, our discoveries will define the molecular basis and role of chromatin inheritance in the maintenance of cell identity and genome architecture.