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.
Highlights
The metazoan genome is compartmentalized in areas of highly interacting chromatin known as topologically associating domains (TADs)
Downstream analysis, involves the characterization of TAD boundaries based on their insulating strength, the enrichment in CCCTC-binding factor (CTCF) binding, proximity to repeat elements and super-enhancers, and, their genetic alterations in cancer
When comparing TAD boundaries detected at successive λ values, we found that higher λ-values produced TAD boundaries that are almost a strict subset of TAD boundaries produced at lower λ values (~94% overlap when considering only the exact bin as a true common TAD boundary, and ~98% when TAD boundaries are allowed to differ by at most one bin between TADs generated for successive λvalues)
Summary
The metazoan genome is compartmentalized in areas of highly interacting chromatin known as topologically associating domains (TADs). Downstream analysis, involves the characterization of TAD boundaries based on their insulating strength, the enrichment in CTCF binding, proximity to repeat elements and super-enhancers, and, their genetic alterations in cancer
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