Neural lineage induction reveals multi-scale dynamics of 3D chromatin organization

Abstract

Regulation of gene expression underlies cell identity. Chromatin structure and gene activity are linked at multiple levels, via positioning of genomic loci to transcriptionally permissive or repressive environments and by connecting cis-regulatory elements such as promoters and enhancers. However, the genome-wide dynamics of these processes during cell differentiation has not been characterized. Using tethered chromatin conformation capture (TCC) sequencing we determined global three-dimensional chromatin structures in mouse embryonic stem (ES) and neural stem (NS) cell derivatives. We found that changes in the propensity of genomic regions to form inter-chromosomal contacts are pervasive in neural induction and are associated with the regulation of gene expression. Moreover, we found a pronounced contribution of euchromatic domains to the intra-chromosomal interaction network of pluripotent cells, indicating the existence of an ES cell-specific mode of chromatin organization. Mapping of promoter-enhancer interactions in pluripotent and differentiated cells revealed that spatial proximity without enhancer element activity is a common architectural feature in cells undergoing early developmental changes. Activity-independent formation of higher-order contacts between cis-regulatory elements, predominant at complex loci, may thus provide an additional layer of transcriptional control.