Abstract
SummaryThe genome of pluripotent stem cells adopts a unique three-dimensional architecture featuring weakly condensed heterochromatin and large nucleosome-free regions. Yet, it is unknown whether structural loops and contact domains display characteristics that distinguish embryonic stem cells (ESCs) from differentiated cell types. We used genome-wide chromosome conformation capture and super-resolution imaging to determine nuclear organization in mouse ESC and neural stem cell (NSC) derivatives. We found that loss of pluripotency is accompanied by widespread gain of structural loops. This general architectural change correlates with enhanced binding of CTCF and cohesins and more pronounced insulation of contacts across chromatin boundaries in lineage-committed cells. Reprogramming NSCs to pluripotency restores the unique features of ESC domain topology. Domains defined by the anchors of loops established upon differentiation are enriched for developmental genes. Chromatin loop formation is a pervasive structural alteration to the genome that accompanies exit from pluripotency and delineates the spatial segregation of developmentally regulated genes.
Highlights
Three-dimensional chromatin topology is an integral facet of transcriptional regulation in development and disease (Bickmore and van Steensel, 2013)
We identified a total of 4,328 chromatin loops in embryonic stem cells (ESCs), neural stem cell (NSC), or both at a resolution of 10 kb (Figures S1C and S1D; STAR Methods)
These observations indicate that chromatin loops are, as expected, generally associated with CTCF occupancy and that CTCF anchored loops are more prevalent in NSCs than in ESCs
Summary
Three-dimensional chromatin topology is an integral facet of transcriptional regulation in development and disease (Bickmore and van Steensel, 2013). Megabase-sized regions of self-association, termed topologically associated domains (TADs) (Dixon et al, 2012; Nora et al, 2012; Sexton et al, 2012), provide a framework for understanding how contacts between cis-regulatory elements are orchestrated. TADs encompass clusters of cognate regulatory elements (Sanyal et al, 2012; Symmons et al, 2014; Tsujimura et al, 2015) and mediate efficient contacts within domains (Symmons et al, 2016). High-resolution chromatin conformation maps have revealed fine structures of TADs (Phillips-Cremins et al, 2013), which are composed of smaller, frequently nested contact domains (Rao et al, 2014)
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