DNA mechanics, in addition to genetic information in DNA, determines who we are, theoretical physicists from Leiden University in The Netherlands have shown. Helmut Schiessel and his group simulated many DNA sequences and found a correlation between mechanical cues and the way DNA is folded.
When James Watson and Francis Crick, along with Rosalind Franklin, identified the structure of DNA molecules in 1953, they revealed that DNA information determines who we are. The sequence of the letters G, A, T and C in the famous double helix determines what proteins are made in our cells.
If you have brown eyes, for instance, this is because a series of letters in your DNA encodes for proteins that build brown eyes. Each cell contains the exact same letter sequence, and yet every organ behaves differently.
How is this possible?
Since the mid 1980s, it has been hypothesized that there is a second layer of information on top of the genetic code consisting of DNA mechanical properties. DNA molecules are much longer than the cells that contain them, and these molecules need to be wrapped up tightly to fit inside a single cell.
This need for compression introduces also an opportunity: the regulation of transcription through a differentiated fashion of DNA packaging.
The way in which DNA is folded determines how the letters are read out, and therefore which proteins are actually made. In each organ, only relevant parts of the genetic information are read.
This has been referred to as the “nucleosome positioning code”. The theory suggests that mechanical cues within the DNA structures determine how preferentially DNA folds.
Second Information Layer Simulation
For the first time, Leiden physicist Helmut Schiessel and his research group provide strong evidence that this second layer of information indeed exists. With their computer code, they have simulated the folding of DNA strands with randomly assigned mechanical cues.
Using a computational approach called the Mutation Monte Carlo method (MMC), which overcomes previous limitations on such attempts, the team showed that the major features of the nucleosome positioning rules can be predicted by the sequence dependent DNA geometry and elasticity.
MMC is based on the standard Metropolis algorithm with two types of Monte Carlo moves: spatial moves and mutation moves. The spatial moves change the DNA conformation and are designed such that the constraints on the middle-frames are not violated. The mutation moves change the bp sequence but keep the DNA configuration fixed. Both moves change the energy, of the two base pair steps involved.
They also report evidence that nucleosomes can be positioned along DNA at arbitrary positions with single base pair precision, even on top of genes.
In other words, it turns out that these mechanical cues actually do determine how the DNA molecule is folded into so-called nucleosomes. Schiessel found correlations between the mechanics and the actual folding structure in the genome of two organisms, baker’s yeast and fission yeast.
This finding reveals evolutionary changes in DNA, mutations that have two very different effects. The letter sequence encoding for a specific protein can change, or the mechanics of the DNA structure can change, resulting in different packaging and levels of DNA accessibility, and therefore differing frequency of production of that protein.
The authors write in the paper:
Here we focused entirely on the nucleosome positioning capability of mechanical information. This is only one aspect of a much wider range of mechanical effects in nucleosomes. The space of ∼1088 wrapping sequences hosts a large range of nucleosomes: nucleosomes that adsorb over- or undertwist via small twist defects (similar to the one observed in a crystal structure), nucleosomes that expose their DNA through thermally induced unwrapping, or hide it, or nucleosomes that unwrap under force along a prescribed path, possibly in a highly asymmetric fashion (recently observed for the 601 sequence). The latter might be important for the interaction with an elongating RNA polymerase. There might be also nucleosomal sequences that are highly sensitive to CpG methylations, forming hotspots for a mechanical epigenetics.
And they conclude with this thought:
Nucleosomes can thus be considered as a highly diverse class of DNA-protein complexes with a near continuous range of physical properties. Special nucleosomes could be designed in silico with our MMC method and their properties probed via in vitro experiments. It will be interesting to study whether well-positioned nucleosomes with special properties reflecting their genomic context have also emerged through a mechanical evolution.
Top Image: The rigid base-pair model is forced, using 28 constraints (indicated by red spheres), into a lefthanded superhelical path that mimics the DNA conformation in the nucleosome. Credit: Leiden Institute of Physics