On the Mechanism and Function of Asymmetric Histone Inheritance

In most tissues, homeostasis is maintained by adult stem cells. These cells have the unique capacity to divide asymmetrically to give rise to both a self-renewing stem cell and a differentiating daughter cell. In the case of the Drosophila germline, Germline Stem Cells (GSCs) divide symmetrically to give rise to both a self-renewing stem cell and a differentiating daughter Gonialblast (GB) cell. The mechanism behind this asymmetric division has long been debated. Previously, in a seminal discovery, the Xin Chen lab found that histones, the primary carriers of the epigenetic information that patterns cell fate, are directly segregated asymmetrically during asymmetric GSC division. In this process, old histones are retained by the GSC while new histones segregate to the GB. This work led to three major questions: to what extent histone inheritance is conserved, what the mechanism is differentially partition histones, and what the exact function of this asymmetric division is. My work has focused on the mechanism and function of this process. Mechanistically, asymmetric histone inheritance is primarily a two-step process in which histones are first differentially incorporated on sister chromatids during DNA replication before these epigenetically distinct sister chromatids are recognized and segregated asymmetrically during mitosis. In our recent work, we have detailed the molecular mechanism by which old and new histones are segregated asymmetrically at the replication fork. We found that low levels of lagging strand polymerases Polα and Polδ, but high levels of RPA drive delayed lagging strand synthesis. This in turn results in old histones recycling preferentially to the leading strand. Functionally, we found that asymmetric histone inheritance is ultimately upstream of cell cycle remodeling. Additionally, related to the function of asymmetric histone inheritance, I tracked histone modifications across the cell cycle and found that a dramatic pattern of chromatin maturation occurs post-replicatively which may control the eventual gene regulatory landscape of the two daughter cells