A comparative analysis of topological domain callers over RNA-associated interactome

Topological domains (TADs) are consecutive genomic locations with denser local interactions to a certain extent, and they are important for cellular gene expression control and modulation. TADs were first identified when studying three-dimensional genomic structures over Hi-C interaction datasets. Many studies have focused on developing approaches in inferring TADs, which led to multiple TAD-caller approaches development. On the other hand, the number of RNA interactome datasets, such as RNA-RNA and RNA-DNA interactions, has recently been increasing. Even though TADs have been extensively studied in Hi-C datasets, they have not been studied across these RNA interactomes. We conducted a systematized comparison of 28 TAD-callers across mammalians over RNA-associated interactomes (RAIs), especially RNA-RNA and RNA-DNA interaction datasets at a high resolution. Our findings highlighted the significant enrichment of Cohesin/CTCF proteins at RNA-TAD boundaries for both RNA-RNA and RNA-DNA interactomes, especially those with corner dots, which are similar to the results for original TADs. The sizes and numbers of RNA-TADs vary significantly between different TAD caller approaches and RNA interactome resolution, suggesting the importance of considering RNA-TADs as hierarchical domains rather than distinct intervals. We examined the core principles and assumptions behind TAD-callers over RNA interactomes. To our best knowledge, this is the first time that many TAD inference methods are adapted to infer TAD-like domains on RNAs. Our results provide valuable guidance in selecting the most suitable methods for TAD inference over RNA interactomes.