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Recent experimental and computational efforts have provided large data sets describing three-dimensional organization of mouse and human genomes and showed the interconnection between the expression profile, epigenetic state, and spatial interactions of loci. These interconnections were utilized to infer the spatial organization of chromatin, including enhancer-promoter contacts, from one-dimensional epigenetic marks. Here, we show that the predictive power of some of these algorithms is overestimated due to peculiar properties of the biological data. We propose an alternative approach, which provides high-quality predictions of chromatin interactions using information on gene expression and CTCF-binding alone. Using multiple metrics, we confirmed that our algorithm could efficiently predict the three-dimensional architecture of both normal and rearranged genomes., (© 2020 Belokopytova et al.; Published by Cold Spring Harbor Laboratory Press.)