The study investigates the dynamic reorganization of chromatin architecture during stem cell differentiation, focusing on human embryonic stem cells (hESCs) and four derived lineages: Mesendoderm (ME), Mesenchymal Stem Cells (MSC), Neural Progenitor Cells (NPC), and Trophoblast-Like Cells (TB). Using Hi-C and 4C experiments, the researchers observed extensive changes in chromatin interactions, particularly within and between topological domains (TADs). Key findings include: 1. **Chromatin Compartment Switching**: 36% of the genome experienced changes in A/B compartments during differentiation, with lineage-specific transitions. Genes changing from A to B compartments tend to show reduced expression, while those changing from B to A tend to show higher expression. 2. **Domain-Level Chromatin Dynamics**: Local alterations in chromatin interaction frequency within TADs were observed, influenced by changes in H3K4me1 density and enhancer elements. Genes within domains with increased intra-domain interaction frequency tend to be up-regulated, while those with decreased interaction frequency tend to be down-regulated. 3. **Allelic Chromatin Organization**: Haplotype-resolved analysis revealed that homologous chromosomes have highly similar A/B compartment patterns, with minor differences at allele-biased regions. Allelic biases in gene expression were identified in 1,787 genes across the five lineages, often reflecting biases in expression levels rather than "on/off" events. 4. **Allelic Enhancer Activity**: Allelic enhancers showed concordant biases in histone acetylation, DNase I hypersensitivity, and DNA methylation. These enhancers were also associated with allele-biased gene expression, suggesting that allele-biased enhancer activity may underlie allele-biased gene expression. The study provides a comprehensive view of chromatin dynamics during stem cell differentiation, highlighting the importance of enhancer elements and allele-specific chromatin states in regulating gene expression.The study investigates the dynamic reorganization of chromatin architecture during stem cell differentiation, focusing on human embryonic stem cells (hESCs) and four derived lineages: Mesendoderm (ME), Mesenchymal Stem Cells (MSC), Neural Progenitor Cells (NPC), and Trophoblast-Like Cells (TB). Using Hi-C and 4C experiments, the researchers observed extensive changes in chromatin interactions, particularly within and between topological domains (TADs). Key findings include: 1. **Chromatin Compartment Switching**: 36% of the genome experienced changes in A/B compartments during differentiation, with lineage-specific transitions. Genes changing from A to B compartments tend to show reduced expression, while those changing from B to A tend to show higher expression. 2. **Domain-Level Chromatin Dynamics**: Local alterations in chromatin interaction frequency within TADs were observed, influenced by changes in H3K4me1 density and enhancer elements. Genes within domains with increased intra-domain interaction frequency tend to be up-regulated, while those with decreased interaction frequency tend to be down-regulated. 3. **Allelic Chromatin Organization**: Haplotype-resolved analysis revealed that homologous chromosomes have highly similar A/B compartment patterns, with minor differences at allele-biased regions. Allelic biases in gene expression were identified in 1,787 genes across the five lineages, often reflecting biases in expression levels rather than "on/off" events. 4. **Allelic Enhancer Activity**: Allelic enhancers showed concordant biases in histone acetylation, DNase I hypersensitivity, and DNA methylation. These enhancers were also associated with allele-biased gene expression, suggesting that allele-biased enhancer activity may underlie allele-biased gene expression. The study provides a comprehensive view of chromatin dynamics during stem cell differentiation, highlighting the importance of enhancer elements and allele-specific chromatin states in regulating gene expression.