Genome-wide prediction of topoisomerase IIβ binding by architectural factors and chromatin accessibility.

Pedro Manuel Martínez-García,Miguel García-Torres,Felipe Cortés-Ledesma,Federico Divina,José Terrón-Bautista,Irene Delgado-Sainz,Francisco Gómez-Vela,Ferhat Ay

doi:10.1371/journal.pcbi.1007814

Abstract

DNA topoisomerase II-β (TOP2B) is fundamental to remove topological problems linked to DNA metabolism and 3D chromatin architecture, but its cut-and-reseal catalytic mechanism can accidentally cause DNA double-strand breaks (DSBs) that can seriously compromise genome integrity. Understanding the factors that determine the genome-wide distribution of TOP2B is therefore not only essential for a complete knowledge of genome dynamics and organization, but also for the implications of TOP2-induced DSBs in the origin of oncogenic translocations and other types of chromosomal rearrangements. Here, we conduct a machine-learning approach for the prediction of TOP2B binding using publicly available sequencing data. We achieve highly accurate predictions, with accessible chromatin and architectural factors being the most informative features. Strikingly, TOP2B is sufficiently explained by only three features: DNase I hypersensitivity, CTCF and cohesin binding, for which genome-wide data are widely available. Based on this, we develop a predictive model for TOP2B genome-wide binding that can be used across cell lines and species, and generate virtual probability tracks that accurately mirror experimental ChIP-seq data. Our results deepen our knowledge on how the accessibility and 3D organization of chromatin determine TOP2B function, and constitute a proof of principle regarding the in silico prediction of sequence-independent chromatin-binding factors.

Highlights

Type II DNA topoisomerases are unique in their ability to catalyze duplex DNA passage, and the only enzymes capable of dealing with superhelical DNA structures, as well as unknotting and decatenating DNA molecules [1]
Once we identified the most predictive features, a generalized TOP2B binding model was built by training on DNase-seq, RAD21 and CTCF data from mouse liver, mouse systems: embryonic fibroblasts (MEFs) and activated B cells using Random Forests [36]
We started by comprehensively assessing the chromatin landscape of TOP2B binding sites in two mouse systems: embryonic fibroblasts (MEFs) and liver

Summary

Introduction

Type II DNA topoisomerases are unique in their ability to catalyze duplex DNA passage, and the only enzymes capable of dealing with superhelical DNA structures, as well as unknotting and decatenating DNA molecules [1]. This places them in a privileged position to integrate and coordinate many aspects of genome organization and metabolism, and have been related to virtually all aspects of chromatin dynamics [2, 3]. TOP2B and RAD21 are spatially organized around CTCF binding sites, forming ordered triple sites that flank the boundaries of TADs in a way that TOP2B is positioned externally and cohesin internally to the domain loop

Methods

Results

Conclusion