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Mourad, R., Li, L., Cuvier, O. (2017). Uncovering direct and indirect molecular determinants of chromatin loops using a computational integrative approach.  PLoS Comput. Biol. 13(5): e1005538.
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Research paper

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.

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PMC5462476 (PMC) (EuropePMC)
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    Publication Type
    PLoS Comput. Biol.
    PLoS Computational Biology
    Publication Year
    1553-7358 1553-734X
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    Genes (12)
    Cell Lines (1)