TADfit is a multivariate linear regression model for profiling hierarchical chromatin domains on replicate Hi-C data

Topologically associating domains (TADs) are fundamental building blocks of three dimensional genome, and organized into complex hierarchies. Identifying hierarchical TADs on Hi-C data helps to understand the relationship between genome architectures and gene regulation. Herein we propose TADfit, a multivariate linear regression model for profiling hierarchical chromatin domains, which tries to fit the interaction frequencies in Hi-C contact matrix with and without replicates using all-possible hierarchical TADs, and the significant ones can be determined by the regression coefficients obtained with the help of an online learning solver called Follow-The-Regularized-Leader (FTRL). Beyond the existing methods, TADfit has an ability to handle multiple contact matrix replicates and find partially overlapping TADs on them, which helps to find the comprehensive underlying TADs across replicates from different experiments. The comparative results tell that TADfit has better accuracy and reproducibility, and the hierarchical TADs called by it exhibit a reasonable biological relevance.