Predicting three-dimensional genome organization with chromatin states.

Yifeng Qi,Bin Zhang,Jian Ma

doi:10.1371/journal.pcbi.1007024

Abstract

We introduce a computational model to simulate chromatin structure and dynamics. Starting from one-dimensional genomics and epigenomics data that are available for hundreds of cell types, this model enables de novo prediction of chromatin structures at five-kilo-base resolution. Simulated chromatin structures recapitulate known features of genome organization, including the formation of chromatin loops, topologically associating domains (TADs) and compartments, and are in quantitative agreement with chromosome conformation capture experiments and super-resolution microscopy measurements. Detailed characterization of the predicted structural ensemble reveals the dynamical flexibility of chromatin loops and the presence of cross-talk among neighboring TADs. Analysis of the model’s energy function uncovers distinct mechanisms for chromatin folding at various length scales and suggests a need to go beyond simple A/B compartment types to predict specific contacts between regulatory elements using polymer simulations.

Highlights

The human genome contains about 2 meters of DNA that is packaged as chromatin inside a nucleus of only 10 micrometers in diameter [1]
Following the maximum entropy approach pioneered by Zhang and Wolynes, we developed a predictive model and parameterized a force field to study chromatin structure and dynamics using genome-wide chromosome conformation capture data (Hi-C)
The model is shown to be transferable across chromosomes and cell types, opens up the opportunity to carry out de novo prediction of genome organization for hundreds of cell types with available epigenomics but not Hi-C data

Summary

Introduction

The human genome contains about 2 meters of DNA that is packaged as chromatin inside a nucleus of only 10 micrometers in diameter [1]. The way in which chromatin is organized in the three-dimensional space, i.e., the chromatin structure, has been shown to play important roles for all DNA-templated processes, including gene transcription, gene regulation, DNA replication, etc [2,3,4]. A detailed characterization of chromatin structure and the physical principles that lead to its establishment will greatly improve our understanding of these molecular processes. The importance of chromatin organization has inspired the development of a variety of experimental techniques for its characterization. Using a combination of nuclear proximity ligation and high-throughput sequencing, chromosome conformation capture and related methods quantify the interaction frequency in three-dimensional space between pairs of genomic loci [5,6], and have revealed many conserved features of chromatin organization. Many of the findings from these cross-linking experiments are being validated and confirmed with microscopy imaging studies that directly probe spatial contacts [12,13,14,15,16,17,18,19,20]

Methods

Results

Discussion

Conclusion