Type II topoisomerases shape multi-scale 3D chromatin folding in regions of positive supercoils (microC).

ABSTRACT: Spatial chromosome architecture is a key factor in gene regulation and genome stability, but how changes in local DNA topology coordinate with global 3D chromosome organization remains poorly understood. Type II topoisomerases (TOP2s) resolve torsional stress and are enriched at chromatin loop anchors and TAD boundaries, where, when trapped, can promote genomic instability. Whether TOP2s relieve topological constraints at these positions and/or participate in 3D chromosome folding, however, remains unclear. Here, we combine 3D genomics, imaging and GapRUN, a method for the genome-wide profiling of positive supercoiling, to assess the role of TOP2s in shaping chromosome organization. Acute TOP2 depletion led to the emergence of new, large-scale contacts at the boundaries between active, positively supercoiled domains and lamina-associated domains (LADs). TOP2-dependent changes were accompanied by remodeling of chromatin-lamina interactions and of gene expression, while at the loop level, TOP2 depletion predominantly remodeled transcriptionally-anchored, positively supercoiled loops. We propose that TOP2s act as a fine-regulator of chromosome folding at multiple scales.

ORGANISM(S): Homo sapiens

PROVIDER: GSE255736 | GEO | 2024/09/19

REPOSITORIES: GEO