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

Chromosomes are giant chain molecules organized into an ensemble of three-dimensional structures characterized with its genomic state and the corresponding biological functions. Despite the strong cell-to-cell heterogeneity, the cell-type specific pattern demonstrated in high-throughput chromosome conformation capture (Hi-C) data hints at a valuable link between structure and function, which makes inference of chromatin domains (CDs) from the pattern of Hi-C a central problem in genome research. Here we present a unified method for analyzing Hi-C data to determine spatial organization of CDs over multiple genomic scales. By applying statistical physics-based clustering analysis to a polymer physics model of the chromosome, our method 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 uncover the principles underlying the multi-scale organization of chromatin chain: (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. Our physically principled interpretation and analysis of Hi-C not only offer an accurate and quantitative view of multi-scale chromatin organization but also help decipher its connections with genome function.