Stratification of TAD boundaries reveals preferential insulation of super-enhancers by strong boundaries

Abstract

The metazoan genome is compartmentalized in areas of highly interacting chromatin known as topologically associating domains (TADs). TADs are demarcated by boundaries mostly conserved across cell types and even across species. However, a genome-wide characterization of TAD boundary strength in mammals is still lacking. In this study, we first use fused two-dimensional lasso as a machine learning method to improve Hi-C contact matrix reproducibility, and, subsequently, we categorize TAD boundaries based on their insulation score. We demonstrate that higher TAD boundary insulation scores are associated with elevated CTCF levels and that they may differ across cell types. Intriguingly, we observe that super-enhancers are preferentially insulated by strong boundaries. Furthermore, we demonstrate that strong TAD boundaries and super-enhancer elements are frequently co-duplicated in cancer patients. Taken together, our findings suggest that super-enhancers insulated by strong TAD boundaries may be exploited, as a functional unit, by cancer cells to promote oncogenesis.

NSD2 overexpression drives clustered chromatin and transcriptional changes in a subset of insulated domains

“…2c). This is consistent with recent studies showing that super-enhancers are enriched with CTCF more frequently than typical enhancers 39,40 .…”

Radiation-Induced DNA Damage and Repair Effects on 3D Genome Organization

“…To assess whether TADs are affected after IR, we identified TAD boundaries and calculated the boundary strength (degree of spatial separation between TADs) for each boundary using both the InsulationScore 36 and the Hicratio method 37 . Both methods determined that TAD boundary strength increases in both BJ-5ta and GM12878 cells 24 hours after IR ( Fig.…”

“…Topologically associating domains (TADs) boundaries were called on 40 kb binned matrices using two methods: the InsulationScore method, as detailed in Crane et al 36 , available as matrix2insulation in the cworld-dekker github package, and the Hicratio method, as described in Gong et al 37 . For the InsulationScore, a 500 kb insulation square size was used, and for the Hicratio method, we used d = 400 kb.…”

Transcriptome and chromatin structure annotation of liver, CD4+ and CD8+ T cells from four livestock species

“…We identified from ≈ 5,400 (chicken) to 11,000 (pig) TADs of variable sizes (150 to 220Kb on average, Table S15 and supplementary data file 12), with a 90-92% genome-wide coverage. To validate these domains predicted by armatus [43] (see Methods), we computed three metrics along the genome: the Directionality Index (DI), to quantify the degree of upstream or downstream interaction bias for any genomic region [44], the local interaction score to represent the insulation profile along the genome [45,46], and the density of in silico predicted CTCF binding sites, expected to be prevalent at TAD boundaries [47,48]. For each species, we observed that the distribution of these three metrics was consistent with previous reports on model organisms (Figure 7 and Figure S26), supporting the relevance of our topological annotation.…”

“…To estimate the structural impact of each TAD boundary, we used the local interaction score as used by [45] and [46] and sometimes referred to as "interaction ratio" or "insulation profile". Within a sliding window of 500kb along the genome (step=10Kb), the insulation score ratio is defined as the proportion of read pairs that span across the middle of the window.…”