Hypothesis-driven probabilistic modelling enables a principled perspective of genomic compartments

The Hi-C method has revolutionized the study of genome organization, yet interpretation of Hi-C interaction frequency maps remains a major challenge. Genomic compartments are a checkered Hi-C interaction pattern suggested to represent the partitioning of the genome into two self-interacting states associated with active and inactive chromatin. Based on a few elementary mechanistic assumptions, we derive a generative probabilistic model of genomic compartments, called deGeco. Testing our model, we find it can explain observed Hi-C interaction maps in a highly robust manner, allowing accurate inference of interaction probability maps from extremely sparse data without any training of parameters. Taking advantage of the interpretability of the model parameters, we then test hypotheses regarding the nature of genomic compartments. We find clear evidence of multiple states, and that these states self-interact with different affinities. We also find that the interaction rules of chromatin states differ considerably within and between chromosomes. Inspecting the molecular underpinnings of a four-state model, we show that a simple classifier can use histone marks to predict the underlying states with 87% accuracy. Finally, we observe instances of mixed-state loci and analyze these loci in single-cell Hi-C maps, finding that mixing of states occurs mainly at the cell level.