Uncovering direct and indirect molecular determinants of chromatin loops using a computational integrative approach

PLoS Comput Biol. 2017 May 23;13(5):e1005538. doi: 10.1371/journal.pcbi.1005538. eCollection 2017 May.


Chromosomal organization in 3D plays a central role in regulating cell-type specific transcriptional and DNA replication timing programs. Yet it remains unclear to what extent the resulting long-range contacts depend on specific molecular drivers. Here we propose a model that comprehensively assesses the influence on contacts of DNA-binding proteins, cis-regulatory elements and DNA consensus motifs. Using real data, we validate a large number of predictions for long-range contacts involving known architectural proteins and DNA motifs. Our model outperforms existing approaches including enrichment test, random forests and correlation, and it uncovers numerous novel long-range contacts in Drosophila and human. The model uncovers the orientation-dependent specificity for long-range contacts between CTCF motifs in Drosophila, highlighting its conserved property in 3D organization of metazoan genomes. Our model further unravels long-range contacts depending on co-factors recruited to DNA indirectly, as illustrated by the influence of cohesin in stabilizing long-range contacts between CTCF sites. It also reveals asymmetric contacts such as enhancer-promoter contacts that highlight opposite influences of the transcription factors EBF1, EGR1 or MEF2C depending on RNA Polymerase II pausing.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Binding Sites
  • Chromatin / chemistry*
  • Chromatin / metabolism*
  • Computational Biology
  • DNA / chemistry*
  • DNA / metabolism*
  • Drosophila
  • Humans
  • Reproducibility of Results


  • Chromatin
  • DNA

Grant support

This work was supported by the University of Toulouse, Fondation pour la Recherche Médicale and the CNRS. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.