Specificity-Determining DNA Triplet Code for Positioning of Human Preinitiation Complex

Abstract

The notion that transcription factors bind DNA only through specific, consensus binding sites has been recently questioned. No specific consensus motif for the positioning of the human preinitiation complex (PIC) has been identified. Here, we reveal that nonconsensus, statistical, DNA triplet code provides specificity for the positioning of the human PIC. In particular, we reveal a highly nonrandom, statistical pattern of repetitive nucleotide triplets that correlates with the genomewide binding preferences of PIC measured by Chip-exo. We analyze the triplet enrichment and depletion near the transcription start site and identify triplets that have the strongest effect on PIC-DNA nonconsensus binding. Using statistical mechanics, a random-binder model without fitting parameters, with genomic DNA sequence being the only input, we further validate that the nonconsensus nucleotide triplet code constitutes a key signature providing PIC binding specificity in the human genome. Our results constitute a proof-of-concept for, to our knowledge, a new design principle for protein-DNA recognition in the human genome, which can lead to a better mechanistic understanding of transcriptional regulation.

Rewiring of transcription factor binding in differentiating human embryonic stem cells is constrained by DNA sequence repeat symmetry

“…The central question that needs to be discussed now is what molecular mechanism responsible for the observed genome-wide dependence of TF binding preferences on DNA repeat symmetry? We have suggested in the past, and validated experimentally for a number of TFs, that certain repetitive DNA sequence elements exert the entropy-dominated TF-DNA binding free energy landscape (5,10,11,13). The main difficulty here stems from the fact that in human ESc (as well as in any other type of cells) there are additional factors, besides the DNA sequence alone, that influence TF-DNA binding preferences.…”

“…We now define the measure for DNA sequence symmetry used to characterize genomic repetitive DNA sequence elements. Specifically, here we use the nucleotide pair-correlation function h aa (x), similar to the one used in our previous work (10). This correlation function, h aa (x), is proportional to the probability to find two nucleotides of the type a separated by the relative distance x along the genome, h aa (x)=(N aa (x)-<N aa (x)> rand )/L.…”

“…In order to quantitatively characterize DNA sequence repeat symmetries, we use one of the simplest possible measures for symmetry, namely, the nucleotide pair correlation function, developed and tested by us recently (10).…”

“…We have shown in the past using both biophysical modeling (5,10,11) and high-throughput in vitro measurements of TF-DNA binding preferences (5) that certain non-consensus, repetitive DNA sequence elements exert an entropy-dominated, statistical interaction potential on TFs. We use the term non-consensus TF-DNA binding free energy in order to describe this statistical interaction potential (5).…”

Physicochemical Foundations of Life that Direct Evolution: Chance and Natural Selection are not Evolutionary Driving Forces

“…Indeed, it is well-established that three-base codon structure of the genetic code contributes to translation efficiency and fidelity and molecular dynamics modeling suggests that charged particles (e.g., ribosomes) interacting with a polymer (e.g., an RNA) via electrostatic forces moves dynamically along the polymer in steps of three monomers [269]. Quite remarkably, there is now increasing evidence that triplets also play a major role in nucleic acid polymer properties and biogenesis which includes the following: (i) Triplets correspond to the width of the minor groove in a double-stranded nucleic acid polymer, and backbone atoms that are in proximity across the minor grove are separated by three nucleotides on the complementary strand [270,271]; (ii) a three-base periodicity has been observed outside coding sequences and provides, for example, specificity for the positioning of the transcription preinitiation complex [272]; (iii) codon bias affects transcription by affecting RNA folding, which favors transcription elongation by reducing pausing and RNA polymerase backtracking [69,[273][274][275]; (iv) intra-and inter-trinucleotide stacking interactions contribute to stabilizing base pairing during the translation process but could have also played a role in replication early in evolution [76]. Collectively, these observations suggest that the three-base genetic code could have been constrained by physical parameters, allowing the simultaneous enhancement of RNA and protein biogenesis [269][270][271]276].…”