Enhancer accessibility and CTCF occupancy underlie asymmetric TAD architecture and cell type specific genome topology

Abstract

Cohesin and CTCF are master regulators of genome topology. How these ubiquitous proteins contribute to cell-type specific genome structure is poorly understood. Here, we explore quantitative aspects of topologically associated domains (TAD) between pluripotent embryonic stem cells (ESC) and lineage-committed cells. ESCs exhibit permissive topological configurations which manifest themselves as increased inter- TAD interactions, weaker intra-TAD interactions, and a unique intra-TAD connectivity whereby one border makes pervasive interactions throughout the domain. Such ‘stripe’ domains are associated with both poised and active chromatin landscapes and transcription is not a key determinant of their structure. By tracking the developmental dynamics of stripe domains, we show that stripe formation is linked to the functional state of the cell through cohesin loading at lineage-specific enhancers and developmental control of CTCF binding site occupancy. We propose that the unique topological configuration of stripe domains represents a permissive landscape facilitating both productive and opportunistic gene regulation and is important for cellular identity.

Systematic Chromatin Architecture Analysis inXenopus tropicalisReveals Conserved Three-Dimensional Folding Principles of Vertebrate Genomes

“…Whether these epigenetic modifications are important for TADs establishment is not determined at this time. However, it is reasonable to speculate that chromatin states can affect the process of cohesin-mediated extrusion as for super-enhancers 44 . Surprisingly, neither the density of genes nor RNA expression was found enriched at the borders of either cluster of TADs (data not shown).…”

Cohesin-Dependent and -Independent Mechanisms Mediate Chromosomal Contacts between Promoters and Enhancers

“…However, genes sharing these domains may have different regulatory wiring and expression patterns ( Hnisz et al., 2016 ; Schoenfelder and Fraser, 2019 ). In addition, active enhancers might themselves function as TAD boundary elements ( Barrington et al., 2019 ; Bonev et al., 2017 ), and contacts between superenhancers recover more rapidly upon reversal of cohesin depletion compared with other chromosomal loops ( Rao et al., 2017 ). These observations suggest that factors acting in cis to DNA regulatory elements are involved in establishing their chromosomal interactions.…”

The interplay between asymmetric and symmetric DNA loop extrusion

“…We previously showed that much like mitotic chromosome compaction, the formation of major features of interphase chromosomes, such as TADs, "dots," and "stripes" requires avoiding unlooped gaps, either between LEFs or between LEFs and TAD boundaries. One-sided extrusion can form TADs and stripes by enhancing local chromatin contacts , as observed in Hi-C experiments (Dixon et al, 2012;Nora et al, 2012;Sexton et al, 2012;Rao et al, 2014;Fudenberg et al, 2016;Vian et al, 2018;Barrington et al, 2019). However, dots (Rao et al, 2014;Krietenstein et al, 2020) can only be generated by "effectively two-sided" loop extrusion because such extrusion can reliably bring together TAD boundaries (e.g., convergently oriented CTCF binding sites (Rao et al, 2014;Guo et al, 2015;Sanborn et al, 2015;de Wit et al, 2015;Vietri Rudan et al, 2015)).…”