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Genome-wide organization of eukaryotic preinitiation complex is influenced by nonconsensus protein-DNA binding.

ABSTRACT: Genome-wide binding preferences of the key components of eukaryotic preinitiation complex (PIC) have been recently measured at high resolution in Saccharomyces cerevisiae by Rhee and Pugh. However, 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 contributes 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 preferences of binding 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 has genome-wide influence on transcriptional frequency.

SUBMITTER: Afek A

PROVIDER: S-EPMC3870814 | biostudies-other | 2013 Mar

REPOSITORIES: biostudies-other

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Genome-wide organization of eukaryotic preinitiation complex is influenced by nonconsensus protein-DNA binding.

Afek Ariel A Lukatsky David B DB

Biophysical journal 20130301 5

Genome-wide binding preferences of the key components of eukaryotic preinitiation complex (PIC) have been recently measured at high resolution in Saccharomyces cerevisiae by Rhee and Pugh. However, 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 contributes statistically at least 2-3 kcal/mol (on average) of addition ...[more]

PMID: 23473494

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Project description:ChIP-Seq, which combines chromatin immunoprecipitation (ChIP) with ultra high-throughput massively parallel sequencing, is increasingly being used for mapping protein-DNA interactions in-vivo on a genome scale. Typically, short sequence reads from ChIP-Seq are mapped to a reference genome for further analysis. Although genomic regions enriched with mapped reads could be inferred as approximate binding regions, short read lengths (approximately 25-50 nt) pose challenges for determining the exact binding sites within these regions. Here, we present SISSRs (Site Identification from Short Sequence Reads), a novel algorithm for precise identification of binding sites from short reads generated from ChIP-Seq experiments. The sensitivity and specificity of SISSRs are demonstrated by applying it on ChIP-Seq data for three widely studied and well-characterized human transcription factors: CTCF (CCCTC-binding factor), NRSF (neuron-restrictive silencer factor) and STAT1 (signal transducer and activator of transcription protein 1). We identified 26 814, 5813 and 73 956 binding sites for CTCF, NRSF and STAT1 proteins, respectively, which is 32, 299 and 78% more than that inferred previously for the respective proteins. Motif analysis revealed that an overwhelming majority of the identified binding sites contained the previously established consensus binding sequence for the respective proteins, thus attesting for SISSRs' accuracy. SISSRs' sensitivity and precision facilitated further analyses of ChIP-Seq data revealing interesting insights, which we believe will serve as guidance for designing ChIP-Seq experiments to map in vivo protein-DNA interactions. We also show that tag densities at the binding sites are a good indicator of protein-DNA binding affinity, which could be used to distinguish and characterize strong and weak binding sites. Using tag density as an indicator of DNA-binding affinity, we have identified core residues within the NRSF and CTCF binding sites that are critical for a stronger DNA binding.

Dataset Information

Genome-wide organization of eukaryotic preinitiation complex is influenced by nonconsensus protein-DNA binding.

Publications

Genome-wide organization of eukaryotic preinitiation complex is influenced by nonconsensus protein-DNA binding.

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