International research team probes mechanics of DNA bending

Using single-molecule fluorescence resonance energy transfer (smFRET), researchers have come closer to understanding the mechanics of DNA bending on a genome-wide scale.

A team of scientists from the United States and Germany has demonstrated that the DNA sequence can affect the ability of DNA to form a loop or bend. They used smFRET to determine the looping rate or cyclization of DNA for a whole genome.

They found cyclizability to be "a measurable mechanical property that can be compared to functional properties of chromosomal DNA."

The importance of measuring the mechanics of DNA is to shed light on how DNA can be compacted so tightly that it fits in the cell nucleus yet remain accessible to cell machinery for the transcription process.

The research was published in the journal Nature on Dec. 16.

Previously, the authors note, "direct measurements of the bendability of specified sequences of interest, such as those that span genomic regions, have not been reported in high throughput."

The researchers developed a method called "loop-seq" to investigate the looping characteristics and their relationship to gene expression, nucleosome positions and codons. Then they used this method to look at how looping was related to transcription in the genome of brewer's yeast, Saccharomyces cerevisiae.

They found that areas of the S. cerevisiae genome with low cyclizability were depleted of nucleosomes, and that the areas with higher cyclizability would be where nucleosomes were positioned. 

"As nucleosome assembly requires extensive DNA bending," the authors state, "the low intrinsic cyclizability of DNA" in stiff areas of the genome are "likely to favor nucleosome depletion."

This is important because nucleosomes provide the scaffold for compaction, which may prevent the DNA from being accessible for the transcription process. Without properly positioned nucleosomes, genes cannot be expressed correctly, which could lead to disease and even death of the organism.

Since DNA sequence affects DNA bending, the researchers wondered if synonymous codons would hinder nucelosome positioning. Codons are the codes for the sequence of three DNA or RNA nucleotides for a particular amino acid.

To test this, the researchers asked what would happen to the DNA cyclizability if codons were replaced with codons that result in the same amino acid but have different DNA sequences.

They found that areas of the S. cerevisiae genome with low cyclizability were depleted of nucleosomes, and that the areas with higher cyclizability would be where nucleosomes were positioned. 

"As nucleosome assembly requires extensive DNA bending," the authors state, "the low intrinsic cyclizability of DNA" in stiff areas of the genome are "likely to favor nucleosome depletion."

The article concludes by noting further research necessary.

"Our measurements suggest that intrinsic cyclizability is functionally important and must have applied selective pressure throughout the evolution of genomes," the article said. "It remains to be determined how genetic information content and the mechanical properties of DNA are linked, and how the sequence-dependent mechanical response of DNA to molecular-scale forces in its immediate environment may have influenced both the slow divergence of organisms and rapid mutations in contexts such as cancer."