This study investigates the molecular dynamics of genome-nuclear lamina (NL) interactions during the differentiation of mouse embryonic stem cells (ESCs) into lineage-committed neural precursor cells (NPCs) and terminally differentiated astrocytes (ACs). High-resolution maps of genome-NL interactions were generated using DamID, revealing a cumulative reorganization of these interactions at hundreds of sites during differentiation. This remodeling affects both individual transcription units and multi-gene regions, and is associated with gene repression. Many genes that move away from the lamina are activated, while others remain inactive but become unlocked for activation in subsequent differentiation steps. The results suggest that NL-genome interactions play a crucial role in controlling gene expression programs during lineage commitment and terminal differentiation. The study also highlights the importance of NL interactions in maintaining cellular identity and the potential for gene activation at later stages of differentiation.This study investigates the molecular dynamics of genome-nuclear lamina (NL) interactions during the differentiation of mouse embryonic stem cells (ESCs) into lineage-committed neural precursor cells (NPCs) and terminally differentiated astrocytes (ACs). High-resolution maps of genome-NL interactions were generated using DamID, revealing a cumulative reorganization of these interactions at hundreds of sites during differentiation. This remodeling affects both individual transcription units and multi-gene regions, and is associated with gene repression. Many genes that move away from the lamina are activated, while others remain inactive but become unlocked for activation in subsequent differentiation steps. The results suggest that NL-genome interactions play a crucial role in controlling gene expression programs during lineage commitment and terminal differentiation. The study also highlights the importance of NL interactions in maintaining cellular identity and the potential for gene activation at later stages of differentiation.