ABSTRACT
The metazoan genome is compartmentalized in megabase-scale areas of highly interacting chromatin known as topologically associating domains (TADs), typically identified by computational analyses of Hi-C sequencing data. TADs are demarcated by boundaries that have been shown to be largely conserved across cell types and even across species. Increasing evidence suggests that the seemingly invariant TADs may exhibit some plasticity in certain cases and their boundary strength can vary. However, a genome-wide characterization of TAD boundary strength in mammals is still lacking. In this study, we use fused two-dimensional lasso as a machine-learning method to first improve Hi-C contact matrix reproducibility and subsequently categorize TAD boundaries based on their strength. We demonstrate that increased boundary strength is associated with elevated levels of CTCF and that TAD boundary insulation scores may differ across cell types. Intriguingly, we also found that super-enhancer elements are preferentially insulated by strong boundaries. Presumably, genetic or epigenetic inactivation of strong boundaries may lead to loss of insulation around super-enhancers, disrupt the physiological transcriptional program and cause disease.