The study presents high-resolution maps of genome-nuclear lamina (NL) interactions during differentiation of mouse embryonic stem cells (ESCs) into neural precursor cells (NPCs) and terminally differentiated astrocytes (ACs). The results show that a basal chromosome architecture in ESCs is cumulatively altered at hundreds of sites during lineage commitment and terminal differentiation. This remodeling involves both individual transcription units and multi-gene regions, and affects many genes that determine cellular identity. Genes that move away from the lamina are often activated, while others remain inactive but become unlocked for activation in a next differentiation step. These findings suggest that NL-genome interactions are involved in controlling gene expression programs during lineage commitment and terminal differentiation. The study also reveals that NL interactions are tightly linked to gene repression, with many genes in the NL being transcriptionally inactive and enriched in repressive histone marks. The results show that NL interactions are highly conserved across different cell types, with a common global architecture of chromosomes characterized by substantial overlapping interactions with the NL through more than 1,000 large genomic domains. The reorganization of these interactions during differentiation involves many genes important for cellular identity. The study further demonstrates that some genes detach from the NL and become unlocked for activation at a later stage. These genes are more likely to become active in subsequent differentiation steps compared to genes with unaltered NL interactions. The findings suggest that the NL plays a key role in the repression of genes and the establishment and switching of gene expression programs during differentiation. The results also indicate that the NL is involved in the regulation of gene expression through its interactions with the genome, and that these interactions are crucial for the proper development and function of cells.The study presents high-resolution maps of genome-nuclear lamina (NL) interactions during differentiation of mouse embryonic stem cells (ESCs) into neural precursor cells (NPCs) and terminally differentiated astrocytes (ACs). The results show that a basal chromosome architecture in ESCs is cumulatively altered at hundreds of sites during lineage commitment and terminal differentiation. This remodeling involves both individual transcription units and multi-gene regions, and affects many genes that determine cellular identity. Genes that move away from the lamina are often activated, while others remain inactive but become unlocked for activation in a next differentiation step. These findings suggest that NL-genome interactions are involved in controlling gene expression programs during lineage commitment and terminal differentiation. The study also reveals that NL interactions are tightly linked to gene repression, with many genes in the NL being transcriptionally inactive and enriched in repressive histone marks. The results show that NL interactions are highly conserved across different cell types, with a common global architecture of chromosomes characterized by substantial overlapping interactions with the NL through more than 1,000 large genomic domains. The reorganization of these interactions during differentiation involves many genes important for cellular identity. The study further demonstrates that some genes detach from the NL and become unlocked for activation at a later stage. These genes are more likely to become active in subsequent differentiation steps compared to genes with unaltered NL interactions. The findings suggest that the NL plays a key role in the repression of genes and the establishment and switching of gene expression programs during differentiation. The results also indicate that the NL is involved in the regulation of gene expression through its interactions with the genome, and that these interactions are crucial for the proper development and function of cells.