From Hi-C Contact Map to Three-dimensional Organization of Interphase Human Chromosomes

TL;DR

This paper introduces HIPPS, a novel theory that derives three-dimensional chromosome structures directly from Hi-C contact maps using polymer physics and maximum entropy principles, revealing heterogeneity in chromosome conformations.

Contribution

The HIPPS method provides a model-free approach to reconstruct 3D chromosome structures solely from contact maps, advancing understanding of chromosome organization.

Findings

Heterogeneous chromosome conformations within single cell types.

Quantitative differences in chromosome structure between normal and cancerous cells.

Predicted chromosome volumes align well with experimental data.

Abstract

The probability of two loci, separated by a certain genome length, being in contact can be inferred using the Chromosome Conformation Capture (3C) method and related Hi-C experiments. How to go from the contact map, a matrix listing the mean contact probabilities between a large number of pairs of loci, to an ensemble of three-dimensional structures is an open problem. A solution to this problem, without assuming an assumed energy function, would be the first step in understanding the way nature has solved the packaging of chromosomes in tight cellular spaces. We created a theory, based on polymer physics characteristics of chromosomes and the maximum entropy principles, referred to as HIPPS (Hi-C-Polymer-Physics-Structures) method, that allows us to calculate the 3D structures solely from Hi-C contact maps. We created an ensemble of 3D structures for the 23 chromosomes from lymphoblastoid cells using the measured contact maps as inputs. The HIPPS method shows that conformations of chromosomes are heterogeneous even in a single cell type. The differences in the conformational heterogeneity of the same chromosome in different cell types (normal as well as cancerous cells) can also be quantitatively discerned using our theory. We validate the method by showing that the calculated volumes of the 23 chromosomes from the predicted 3D structures are in good agreement with experimental estimates. Because the method is general, the 3D structures for any species may be calculated directly from the contact map without the need to assume a specific polymer model, as is customarily done.