UC Santa Cruz

The goal of my thesis was to resolve the epigenetic mechanisms that govern hematopoietic stem cell (HSC) multipotency and differentiation. Hematopoiesis describes the essential function of constantly producing every type of blood cell daily throughout life. To accomplish this multilineage differentiation, the HSC and intermediate progenitors require precise temporal expression and control of cell-type-specific genes throughout differentiation. Cis-regulatory elements (CREs) regulate the temporal expression of these genes during hematopoiesis. The CREs themselves are regulated by altering the accessibility of those elements to transcription factor binding. The priming of CREs for transcription factor binding and gene activation without active expression allows a cell to be developmentally competent for specific cell types and act upon inductive signals to specify cell fate. Understanding the dynamics of cis-element accessibility is essential to understanding the mechanisms of stem fate decisions in hematopoiesis. My thesis project focused on characterizing the CRE accessibility dynamics in hematopoiesis to uncover regulators of fate decisions and then functionally interrogating the CREs to elucidate their function in hematopoiesis. Understanding these mechanisms during normal hematopoiesis will allow us to better understand the pathogenesis of hematological malignancies and manipulate the system to control lineage output.