The Role of the GSK3 Inhibition-Tcf7l1 Axis in Facilitating Exit from Naive Pluripotency

This thesis dissertation examines events which allow embryonic stem cells (ESC) to progress from early or “naïve” pluripotency, a state characterized by propensity for self-renewal, to late or “primed” pluripotency, whence ESC become competent to divide into lineage-specifying cells. This work occurs in two sections. The first section examines the role of the GSK3i-Tcf/Lef axis in the exit from naïve pluripotency. The second section elucidates an epigenetic mechanism by which Tcf7l1 drives exit from naïve pluripotency. Based on conclusions from this work, I propose that Tcf7l1-mediated enhancer decommissioning accommodates the need for pluripotent cells to rapidly alter their response to differentiation signals in the progression towards gastrulation, a likely mechanism by which Wnt/β-catenin signaling controls other stem cell lineage decisions.