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

Abstract

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.

Structural basis for the preservation of a subset of topologically associating domains in interphase chromosomes upon cohesin depletion

“…( i ) Contact map for the 8 Mbp region ((44–52) Mb) with the upper (lower) triangle corresponding to simulations (experiments). ( j ) On the right is an Illustration of the TADs, identified using the Multi-CD method ( Bak et al, 2021 ). The dark-red circles are the positions of the loop anchors detected in the Hi-C experiment, which are formed by two CTCF motifs.…”

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

“…(i) Contact map for the 8 Mbp region ((44-52)Mb) with the upper (lower) triangle corresponding to simulations (experiments). (j) On the right is an Illustration of the TADs, identified using the Multi-CD method [72]. The dark-red circles are the positions of the loop anchors detected in the Hi-C experiment, which are formed by two CTCF motifs.…”

ENT3C: an entropy-based similarity measure for Hi-C and micro-C derived contact matrices

“…In addition, sequence-driven noise in contact matrices arises from nucleotide composition and mappability. Because it helps mitigate stochastic fluctuations or experimental artifacts by emphasizing consistent patterns from which biologically meaningful features like A/B compartments can be determined, contact matrices are often transformed into Pearson correlation matrices where each entry is the correlation coefficient between the corresponding row and column in the contact matrix (2,5,6). Quantifying the similarity between Hi-C and micro-C contact matrices is essential for understanding how the 3D genome organization differs among various cell lines or under different biological conditions.…”

“…Chromosome conformation capturing (3C-based) (1) has been pivotal in the discovery of hallmarks of 3D genome organization such as compartments, compartmental domains, topologically associating domains and chromatin loops, that each play distinct roles in regulating gene expression. Specifically, Hi-C (2–4) and micro-C (5) assays ligate DNA fragments in 3D proximity to one another and use deep sequencing to infer chromatin interaction frequencies. These data are then typically summarized in a contact matrix whereby the genome is binned into fixed-sized loci and each entry in the matrix is the estimated interaction between a pair of loci.…”