Enhancer accessibility and CTCF occupancy underlie cell-type specific genome topology

Chromosome topology has been profiled in pluripotent embryonic stem cells (ESC) and differentiated cells, revealing similar topological configurations despite the unique chromatin and regulatory environment of ESCs. How such topological similarities account for cell fate differences is not well understood. We explored quantitative aspects of topologically associated domains (TAD) between ESC and lineage-committed cells. Our results indicate that ESC genomes exhibit permissive topological configurations. We find widespread changes in intra-TAD connectivity and inter-TAD insulation during differentiation. Further, insulation often varies between borders of the same TAD, resulting in a previously uncharacterised but prevalent topology in ESC genomes (here termed ‘asymmetric’ or aTADs). aTADs have a ‘non-permeable’, strongly insulating border on one end and a ‘permeable’ border with weak and variable insulation on the other. Enhancers, cohesin and NIPBL are enriched at the non-permeable aTAD border while the permeable border has several low-occupancy CTCF binding sites. Our results reveal distinct mechanisms of aTAD formation and suggest specific regulation of, and biological function for aTADs. Indeed, developmental changes to CTCF occupancy and gene expression contribute to a switch of the aTAD landscape into less flexible topological configurations while also revealing the presence of aTADs in differentiated cells. We propose that the unique topological configurations of aTADs facilitates a novel type of permissive regulatory landscape and that cell-type specific regulation of border permeability (not necessarily presence) has an important role in gene expression important for cellular identity.