The pluripotent genome in three dimensions is shaped around pluripotency factors

Using 4C technology, higher-order topological features of the pluripotent genome are identified; in pluripotent stem cells, Nanog clusters specifically with other pluripotency genes and this clustering is centred around Nanog-binding sites, suggesting that Nanog helps to shape the three-dimensional structure of the pluripotent genome and thereby contributes to the robustness of the pluripotent state. Shaping the genome for pluripotency The three-dimensional structure of the genome is emerging as an additional layer of chromatin organization that is important for gene regulation. Using 4C sequencing technology combined with chromatin factor binding data, Wouter de Laat and colleagues have identified unique higher-order topological features of the pluripotent stem-cell genome. Genomic clusters of binding sites for the pluripotency factors Nanog, Oct4 and Sox2 show a pronounced capacity to contact each other in a pluripotency-specific manner. The authors suggest that the observed spatial clustering of these binding sites in pluripotent stem cells may enhance the transcription efficiency of nearby genes, thereby contributing to the robustness of the pluripotent state. It is becoming increasingly clear that the shape of the genome importantly influences transcription regulation. Pluripotent stem cells such as embryonic stem cells were recently shown to organize their chromosomes into topological domains that are largely invariant between cell types 1 , 2 . Here we combine chromatin conformation capture technologies with chromatin factor binding data to demonstrate that inactive chromatin is unusually disorganized in pluripotent stem-cell nuclei. We show that gene promoters engage in contacts between topological domains in a largely tissue-independent manner, whereas enhancers have a more tissue-restricted interaction profile. Notably, genomic clusters of pluripotency factor binding sites find each other very efficiently, in a manner that is strictly pluripotent-stem-cell-specific, dependent on the presence of Oct4 and Nanog protein and inducible after artificial recruitment of Nanog to a selected chromosomal site. We conclude that pluripotent stem cells have a unique higher-order genome structure shaped by pluripotency factors. We speculate that this interactome enhances the robustness of the pluripotent state.