A unified framework for inferring the multi-scale organization of chromatin domains from Hi-C

Identifying chromatin domains (CDs) from high-throughput chromosome conformation capture (Hi-C) data is currently a central problem in genome research. Here we present a unified algorithm, Multi-CD, which infers CDs at various genomic scales by leveraging the information from Hi-C. By integrating a model of the chromosome from polymer physics, statistical physics-based clustering analysis, and Bayesian inference, Multi-CD identifies the CDs that best represent the global pattern of correlation manifested in Hi-C. The multi-scale intra-chromosomal structures compared across different cell types allow us to glean the principles of chromatin organization: (i) Sub-TADs, TADs, and meta-TADs constitute a robust hierarchical structure. (ii) The assemblies of compartments and TAD-based domains are governed by different organizational principles. (iii) Sub-TADs are the common building blocks of chromosome architecture. CDs obtained from Multi-CD applied to Hi-C data enable a quantitative and comparative analysis of chromosome organization in different cell types, providing glimpses into structure-function relationship in genome.