Sequence Dependence of Transcription Factor-Mediated DNA Looping

TL;DR

This study combines experiments and models to understand how DNA sequence influences short-range DNA looping, a key process in gene regulation, revealing that nucleosome-favorable sequences do not significantly affect looping behavior.

Contribution

It provides a quantitative analysis of DNA looping dependence on sequence and other parameters, integrating experimental data with a statistical mechanical model.

Findings

DNA looping depends on transcription factor binding strength, concentration, length, and sequence.

Sequences favoring nucleosome formation do not significantly alter DNA looping.

Short length scale DNA mechanics differ from nucleosome formation mechanics.

Abstract

DNA is subject to large deformations in a wide range of biological processes. Two key examples illustrate how such deformations influence the readout of the genetic information: the sequestering of eukaryotic genes by nucleosomes, and DNA looping in transcriptional regulation in both prokaryotes and eukaryotes. These kinds of regulatory problems are now becoming amenable to systematic quantitative dissection with a powerful dialogue between theory and experiment. Here we use a single-molecule experiment in conjunction with a statistical mechanical model to test quantitative predictions for the behavior of DNA looping at short length scales, and to determine how DNA sequence affects looping at these lengths. We calculate and measure how such looping depends upon four key biological parameters: the strength of the transcription factor binding sites, the concentration of the transcription factor, and the length and sequence of the DNA loop. Our studies lead to the surprising insight that sequences that are thought to be especially favorable for nucleosome formation because of high flexibility lead to no systematically detectable effect of sequence on looping, and begin to provide a picture of the distinctions between the short length scale mechanics of nucleosome formation and looping.