Long-range chromatin contacts in embryonic stem cells reveal a role for pluripotency factors and polycomb proteins in genome organization.

The relationship between three-dimensional organization of the genome and gene-regulatory networks is poorly understood. Here, we examined long-range chromatin interactions genome-wide in embryonic stem cells (ESCs), iPSCs, and fibroblasts, and uncover a pluripotency-specific genome organization that is gradually re-established during reprogramming. Our data confirm that long-range chromatin interactions are primarily associated with the spatial segregation of open and closed chromatin, defining overall chromosome conformation. Additionally, we identified two further levels of genome organization in ESCs characterized by co-localization of regions with high pluripotency factor occupancy and strong enrichment for Polycomb proteins/H3K27me3, respectively. Underlining the independence of these networks and their functional relevance for genome organization, loss of the Polycomb protein Eed diminishes interactions between Polycomb-regulated regions without altering overarching chromosome conformation. Together, our data highlight a pluripotency-specific genome organization in which Nanog and H3K27me3 occupy distinct nuclear spaces and reveal a role for cell type-specific gene-regulatory networks in genome organization.

基因组的三维结构与基因调控网络之间的关系鲜为人知。在此，我们在胚胎干细胞（ESCs）、诱导多能干细胞（iPSCs）和成纤维细胞中对全基因组的长程染色质相互作用进行了检测，并揭示了一种在重编程过程中逐渐重新建立的多能性特异性基因组结构。我们的数据证实，长程染色质相互作用主要与开放染色质和闭合染色质的空间分离相关，这决定了整体的染色体构象。此外，我们在ESCs中还确定了另外两个层次的基因组结构，其特征分别是高多能性因子占据区域的共定位以及多梳蛋白/H3K27me3的高度富集。多梳蛋白Eed的缺失会减少多梳调控区域之间的相互作用，但不会改变整体的染色体构象，这凸显了这些网络的独立性及其与基因组结构的功能相关性。总之，我们的数据强调了一种多能性特异性基因组结构，其中Nanog和H3K27me3占据不同的核空间，并揭示了细胞类型特异性基因调控网络在基因组结构中的作用。