Global Reorganization of Chromatin Architecture during Embronic Stem Cell Differentiation

The 3D organization of the genome is important for regulation of diverse nuclear processes ranging from transcription to DNA replication. Knowledge of the higher order chromatin structure is critical for understanding mechanisms of gene regulation by long-range control elements such as enhancers and insulators. We describe high resolution, genome-wide dynamic chromatin interaction maps in human embryonic stem cells (hESC) as they differentiate into four distinct embryonic cell lineages. Extensive reorganization of higher-order chromatin structure occurs during hESC differentiation. In this process, topological domains remain largely intact but inter-domain association patterns change dramatically, coincident with widespread changes in chromatin state and gene expression. Moreover, using proximity ligation sequencing to generate chromosome span haplotypes, widespread allele biased gene activities are detected. The allelic gene expression patterns can be correlated to epigenetic state at distal enhancers, supporting the role of these elements in regulating gene expression over a distance.