Genome-wide organization of eukaryotic pre-initiation complex is influenced by nonconsensus protein-DNA binding

TL;DR

This study demonstrates that nonconsensus protein-DNA interactions significantly influence the binding preferences of the eukaryotic pre-initiation complex across the genome, affecting transcription regulation and promoter architecture.

Contribution

It reveals the role of nonconsensus binding in PIC specificity and provides a quantitative free energy landscape correlating with genome-wide occupancy patterns.

Findings

Nonconsensus binding contributes 2-3 kcal/mol of free energy per promoter.

Strong correlation between free energy landscape and PIC occupancy.

Nonconsensus binding influences transcriptional frequency genome-wide.

Abstract

Genome-wide binding preferences of the key components of eukaryotic pre-initiation complex (PIC) have been recently measured with high resolution in Saccharomyces cerevisiae by Rhee and Pugh (Nature (2012) 483:295-301). Yet the rules determining the PIC binding specificity remain poorly understood. In this study we show that nonconsensus protein-DNA binding significantly influences PIC binding preferences. We estimate that such nonconsensus binding contribute statistically at least 2-3 kcal/mol (on average) of additional attractive free energy per protein, per core promoter region. The predicted attractive effect is particularly strong at repeated poly(dA:dT) and poly(dC:dG) tracts. Overall, the computed free energy landscape of nonconsensus protein-DNA binding shows strong correlation with the measured genome-wide PIC occupancy. Remarkably, statistical PIC binding preferences to both TFIID-dominated and SAGA-dominated genes correlate with the nonconsensus free energy landscape, yet these two groups of genes are distinguishable based on the average free energy profiles. We suggest that the predicted nonconsensus binding mechanism provides a genome-wide background for specific promoter elements, such as transcription factor binding sites, TATA-like elements, and specific binding of the PIC components to nucleosomes. We also show that nonconsensus binding influences transcriptional frequency genome-wide.