Semi-nonparametric modeling of topological domain formation from epigenetic data

Abstract

Background: Hi-C experiments capturing the 3D genome architecture have led to the discovery of topologically-associated domains (TADs) that form an important part of the 3D genome organization and appear to play a role in gene regulation and other functions. Several histone modifications have been independently associated with TAD formation, but their combinatorial effects on domain formation remain poorly understood at a global scale. Results: We propose a convex semi-nonparametric approach called nTDP based on Bernstein polynomials to explore the joint effects of histone markers on TAD formation as well as predict TADs solely from the histone data. We find a small subset of modifications to be predictive of TADs across species. By inferring TADs using our trained model, we are able to predict TADs across different species and cell types, without the use of Hi-C data, suggesting their effect is conserved. This work provides the first comprehensive joint model of the effect of histone markers on domain formation. Conclusions: Our approach, nTDP, can form the basis of a unified, explanatory model of the relationship between epigenetic marks and topological domain structures. It can be used to predict domain boundaries for cell types, species, and conditions for which no Hi-C data is available. The model may also be of use for improving Hi-C-based domain finders.