Imagine if understanding how DNA folds could unlock new breakthroughs in medicine — researchers have now developed a multilayer model that explains the intricate folding and packaging of chromatin, accounting for the complex physical, chemical, and structural constraints of chromosomes.
DNA is packed into chromatin by wrapping around proteins called histones, forming small units called nucleosomes — like “beads on a string,” with the DNA as the string. These nucleosomes coil into thicker fibers, which then twist and fold into tightly packed chromosomes.
In each human cell, the DNA stretches about two meters long, yet through this intricate compaction process, it fits neatly inside a nucleus that is much smaller than a strand of human hair. This efficient system allows the long strands of DNA to fit neatly inside the cell’s nucleus while keeping it organized and accessible for important tasks like gene expression and cell division.
Over the years, researchers have developed many models to explain the folding mechanism of DNA, but none have been able to truly capture it. A better understanding of DNA packaging would help researchers understand how heredity is practically modulated and realized into discernible features.
“I tried to demonstrate that the detailed analysis of the difficulties for the high compaction of the enormously long genomic DNA molecules can help to construct a physically consistent structural model of chromosomes,” wrote Joan-Ramon Dabon, a researcher at Universitat Autònoma de Barcelona, in Spain, in an email.
Where current models come up short
Existing models depict chromatin with long chromatin and empty spaces lacking the repeating nucleosome unit, which are at odds with the “sardine can” arrangement required to fit large amounts of DNA. “There are models that do not consider the self-associative properties of nucleosomes and cannot explain the elongated cylindrical shape of chromosomes,” said Daban. Previous models often overlooked important constraints based on experimental findings and computer simulations.
To create a realistic model of chromatin folding, researchers need to take into account the contours of chromatin and how its shape changes as it folds, bends, and twists. Chromatin models need to also evaluate how long DNA strands are protected from entangling and breakage, while allowing for easy unspooling to facilitate gene expression.
Through imaging microscopy studies carried out in Daban’s lab, the researchers found that chromatin forms flat, stacked layers where each layer is as thick as a single sheet of nucleosomes. The thickness of each layer led scientists to suggest that in chromosomes, the chromatin folds in a regular pattern with many layers of nucleosomes neatly stacked along the length of the chromosome.
This multilayer chromatin folding pattern also does away with significant tangling, as would be otherwise expected in any lengthy cable or fiber.
“The organization of DNA in chromosomes can be explained from repetitive interactions between nucleosomes,” said Daban. “A multilayer organization of chromatin provides a structural framework that can support the epigenetic mechanisms of gene regulation and is compatible with DNA replication and repair, and chromosome duplication.”
Multilayering provides deeper insights
Epigenetic mechanisms are akin to switches that control which genes are turned on or off, and are controlled by our environment, diet, and experiences. Even without changing the DNA itself, the signals can be passed down to future generations. The high-level organization is central to how epigenetic mechanisms control gene regulation, and better models of DNA packaging will help researchers understand these mechanisms.
Most models, except for the multilayer chromatin model proposed by Daban, struggle to explain certain chromosome features, such as the light and dark bands observed when chromosomes are stained and viewed under a microscope, or the structural changes seen in genetic studies when chromosome segments break and swap places.
For example, competing models, like the fibrillar model, do not adequately account for the orientation of DNA folding or the thickness and width of individual layers, which appear as distinct bands in microscopy.
In Daban’s model, the chromosome behaves like a liquid crystal with a layered structure, allowing the chromatin layers to glide smoothly against each other and avoid tangling.
While an interesting step forward, additional experimental evidence is needed to further validate this multilayer chromatin model. If supported, this model could provide a framework for understanding crucial processes such as gene activation and silencing, as well as DNA replication and repair, which are fundamental to advancing biomedical research.
“My dream is that the multilayer model will be fully accepted and that future textbooks will include it to explain many fundamental aspects of molecular cell biology and genetics,” added Daban,
Reference: Joan-Ramon Daban, et al., Rethinking Models of DNA Organization in Micrometer-Sized Chromosomes from the Perspective of the Nanoproperties of Chromatin Favoring a Multilayer Structure, Small Structures (2024). DOI: https://doi.org/10.1002/sstr.202400203
Feature image credit: digitale.de on Unsplash
