Efficient Hi-C inversion facilitates chromatin folding mechanism discovery and structure prediction.

and genome-wide. However, the polymer topology of chromosomes complicates Hi-C data analysis, which often employs sophisticated algorithms without explicitly accounting for the disparate processes affecting each interaction frequency. In contrast, we introduce a computational framework based on polymer physics arguments that efficiently removes the correlation between Hi-C interaction frequencies and quantifies how each local interaction influences genome folding globally. This framework facilitates the identification of mechanistically important interactions and the prediction of three-dimensional genome structures.