Embryonic stem cells (ESCs) are pluripotent, meaning that they can differentiate into all major lineages of the embryo. This powerful property is encoded at the epigenetic level, where lineage-specific gene regulatory elements exist in accessible but inactive ‘poised’ or ‘primed’ epigenetic states. When ESCs commit to differentiation towards a particular lineage, active regulatory regions associated with the pluripotent state and poised/primed regulatory regions associated with alternative lineages are decommissioned and undergo silencing – however, the details of how this occurs at the molecular level is still a major question in biology. We performed multi-omics studies of human ESCs differentiated in vitro to define the molecular events that occur during epigenetic decommissioning. We found that the pro-differentiation transcription factor GATA3 is rapidly upregulated in response to BMP pathway signalling and acts to remodel the cellular epigenetic landscape by both activating and silencing regulatory regions. We used CRISPR/Cas9 genome editing strategies to modulate GATA3 activity in 2D and 3D ESC-based models of human gastrulation and found that activity of GATA3 is required to mediate regulatory region decommissioning in a lineage-specific manner, as well as instigate patterning of the ESC population through upregulation of growth factor WNT3. Ongoing work now further explores the mechanisms that mediate epigenetic decommissioning during development.