Quantification of Cooperativity in Heterodimer-DNA Binding Improves the Accuracy of Binding Specificity Models.

The Journal of Biological Chemistry
Alina IsakovaBart Deplancke

Abstract

Many transcription factors (TFs) have the ability to cooperate on DNA elements as heterodimers. Despite the significance of TF heterodimerization for gene regulation, a quantitative understanding of cooperativity between various TF dimer partners and its impact on heterodimer DNA binding specificity models is still lacking. Here, we used a novel integrative approach, combining microfluidics-steered measurements of dimer-DNA assembly with mechanistic modeling of the implicated protein-protein-DNA interactions to quantitatively interrogate the cooperative DNA binding behavior of the adipogenic peroxisome proliferator-activated receptor γ (PPARγ):retinoid X receptor α (RXRα) heterodimer. Using the high throughput MITOMI (mechanically induced trapping of molecular interactions) platform, we derived equilibrium DNA binding data for PPARγ, RXRα, as well as the PPARγ:RXRα heterodimer to more than 300 target DNA sites and variants thereof. We then quantified cooperativity underlying heterodimer-DNA binding and derived an integrative heterodimer DNA binding constant. Using this cooperativity-inclusive constant, we were able to build a heterodimer-DNA binding specificity model that has superior predictive power than the one based on a re...Continue Reading

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Citations

Jul 30, 2016·Cell·Bart DeplanckeVincent Gardeux
Feb 7, 2017·Obesity Reviews : an Official Journal of the International Association for the Study of Obesity·R N PradhanB Deplancke
Jan 17, 2017·Nature Methods·Alina IsakovaBart Deplancke
Feb 1, 2017·Proceedings of the National Academy of Sciences of the United States of America·Sharon R GrossmanEric S Lander
May 15, 2018·FASEB Journal : Official Publication of the Federation of American Societies for Experimental Biology·Veronica CeccarelliAlba Vecchini

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Methods Mentioned

BETA
chip
equilibrium binding
ChIP-seq
ChIP-chip
chips

Software Mentioned

JASPAR
MAFFT
enoLOGOS
MITOMI

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