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

Abstract

Identifying chromatin domains (CDs) from Hi-C data is currently a central problem in genome research. Here we present Multi-CD (https://github.com/multi-cd), a unified method to discover CDs at various genomic scales. Integrating approaches from polymer physics, financial market fluctuation analysis and Bayesian inference, Multi-CD identifies the CDs that best represent the global pattern of correlation manifested in Hi-C, and reveals the multi-scale structure of chromosome. At each scale, the CDs are consistent with the results of existing methods, as well as with biological data from independent sources. CD solutions compared across different scales and cell types allow us to quantify the hierarchy between four major families of CDs, and 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 distinct organizational principles. (iii) Sub-TADs are the common building blocks of chromosome architecture. CDs acquired from our interpretation of Hi-C data using Multi-CD not only provide new insights into chromatin organization, but also offer a quantitative account for its cell-type-dependence and function.with γ ij = (σ ii + σ jj − 2σ ij )/2, where σ ij (= δr i · δr j ) is the positional covariance, determined by the topology of polymer network [42]. Indeed, distance distributions measured using fluorescence measurement between chromatin loci justifies this hypothesis (see Fig. S1). Importantly, our interpretation of chromosome conformation as a locally equilibrated, quasi-stable polymer network enables a one-to-one mapping of the contact probability p ij = rc 0 dxP (x; γ ij ) to the positional covariance σ ij , and hence to the cross-correlation matrix, (C) ij = σ ij / √ σ ii σ jj (see Methods). The cross-correlation matrix C normalizes the wide numer-

Structural basis for preservation of a subset of Topologically Associating Domains in Interphase Chromosomes upon cohesin depletion

“…Identification of the TADs depends on the resolution of the Hi-C data, and the method used to annotate them 4,7,8,37,38 . We used the Multi-Chromatin Domain (Multi-CD) method 39 to visualize the TADs and the sub-TAD structures. SI Fig.1j and m illustrate that a subset of TADs is defined by the CTCF loops, whereas others are not associated with loops.…”

“…Topologically associating domains (TADs): Identification of the TADs depends on the resolution of the Hi-C data, and the method used to annotate them 4,7,8,46,47 . We used the Multi-Chromatin Domain (Multi-CD) method 48 to visualize the TADs and the sub-TAD structures. SI Fig.…”

Mapping the semi-nested community structure of 3D chromosome contact networks

“…However, this conclusion is inconsistent with the competing mechanisms that seem to form TADs and A/B compartments: loop extrusion and phase-separation 17;18 . Third, in a recent paper 19 , researchers fit a Gaussian polymer model to Hi-C data and recovered several established sub-structures—TADs, subTADs, A/B compartments etc.—showing that they were not perfectly hierarchical.…”