Examining the dynamics of three-dimensional genome organization with multitask matrix factorization

Three-dimensional (3D) genome organization, which determines how the DNA is packaged inside the nucleus, has emerged as a key component of the gene regulation machinery. High-throughput chromosome conformation data sets, such as Hi-C, have become available across multiple conditions and time points, offering a unique opportunity to examine changes in 3D genome organization and link them to phenotypic changes in normal and disease processes. However, systematic detection of higher-order structural changes across multiple Hi-C data sets remains a major challenge. Existing computational methods either do not model higher-order structural units or cannot model dynamics across more than two conditions of interest. We address these limitations with tree-guided integrated factorization (TGIF), a generalizable multitask nonnegative matrix factorization (NMF) approach that can be applied to time series or hierarchically related biological conditions. TGIF can identify large-scale changes at the compartment or subcompartment levels, as well as local changes at boundaries of topologically associated domains (TADs). Based on benchmarking in simulated and real Hi-C data, TGIF boundaries are more accurate and reproducible across differential levels of noise and sources of technical artifacts, and are more enriched in CTCF. Application to three multisample mammalian data sets shows that TGIF can detect differential regions at compartment, subcompartment, and boundary levels that are associated with significant changes in regulatory signals and gene expression enriched in tissue-specific processes. Finally, we leverage TGIF boundaries to prioritize sequence variants for multiple phenotypes from the NHGRI GWAS catalog. Taken together, TGIF is a flexible tool to examine 3D genome organization dynamics across disease and developmental processes.