SUNDAY, 30 NOVEMBER 2025

Maria Julia Maristany explores how our genome organises itself without a blueprint.


Say you take the entire railway network of the UK, made up of thousands of miles of tracks, countless train stations, and complex crossings and junctions, just to compress the whole thing into a space similar to that of Trafalgar Square. Not only must all the tracks fit, but they also need to remain fully functional: trains should still travel without interruptions, stopping at the right platforms and switching directions when needed, all while compressed inside of a space that is one hundred thousand times smaller! That’s precisely the challenge our genome faces. Trafalgar Square? The cellular nucleus. And the train? Our DNA.

The human DNA measures just over two meters when fully stretched out. The amazing part is that it must fit inside the microscopic nucleus of a single cell many, many orders of magnitude smaller. Surprisingly, our DNA doesn’t remain static and immobile; it continuously alternates between compact and expanded states to ensure that the required genes are available when the cell needs them to be. Not only that, but our genome’s challenge is even greater: every cell in our body has the same DNA. So, how does a cell know if it is fated to be a brain or a lung cell? The answer to this complex question actually lies in the shape of our DNA’s particular nuclear packing.

Whenever I think about the tightly packed DNA within a cellular nucleus, I cannot help but picture my cluttered office cable drawer: it usually takes me about 20 minutes to find the correct HDMI cable I need! So, how can the cell achieve its remarkable genetic organisation without its nucleus turning into a fully tangled mess? The answer lies in a physics phenomenon: phase separation. More specifically, phase separation of chromatin.

Before going any further, we need to talk about chromatin. Chromatin is a complex of DNA and protein cores, that act as molecular spools, wrapping DNA into tidy, compact structures. Depending on how tightly packed it is, chromatin can either silence genes or make them accessible for gene expression. Rather than arranging itself into rigid tracks, chromatin organises itself into dynamic compartments, rapidly forming and dissolving like small droplets of oil in water. The ability to transition between these states is what allows life to function at the molecular level. Let’s explore how this hidden phase transition in our cells shapes scientists’ understanding of genetics, disease, and the very essence of life.

If you’ve ever seen oil droplets in water, a lava lamp, or even an oily salad dressing, then you have seen a process called phase separation. Instead of mixing evenly, some molecules can spontaneously gather together and form droplets, or phases, that are separated from their environment. This self-organising behaviour turns out to be fundamental for the manner our DNA is packaged.

Chromatin, DNA and proteins don’t randomly float around in the nucleus. Instead, they can form these exact droplet-like compartments, called biomolecular condensates, where different parts of the genome are concentrated into different regions. This property allows the cell to quickly switch between active and inactive states, determining which genes are accessible and which are locked away at any given time. Chromatin’s liquid-like properties mean these compartments can form and dissolve dynamically rather than being fixed, unmovable, structures. Depending on what the cell needs, chromatin can condense tightly to silence genes or dissolve to activate them.



Why is This important?

  • In stem cells, chromatin remains fluid and dynamic, allowing cells to become anything from neurons to muscle cells.
  • In specialised, differentiated cells, phase separation of certain regions of the genome aids in locking away genes that are not needed.
  • If chromatin’s phase behaviour goes wrong, it can lead to diseases like cancer or neurodegeneration, where genes get switched on or off incorrectly.




Phase separation in simple liquids like oil and water is easy to observe- but how do we see something similar happening inside a tiny cell nucleus, completely invisible to the naked eye? Scientists use a combination of advanced microscopy techniques and biochemical experiments to track chromatin dynamics.

One key technique is fluorescence microscopy, in which specific chromatin proteins are labelled with glowing markers. Under the right conditions, these proteins spontaneously showcase bright, droplet-like structures in the nucleus, visible under a microscope. This confirms that chromatin can indeed phase-separate.

Another method involves optogenetics, in which researchers use light to trigger phase separation in live cells. They observe in real time how chromatin compartments form and dissolve. By tweaking the properties of chromatin-associated molecules, they can test how different conditions affect gene regulation, potentially offering new ways to control genetic activity.

But even with the most advanced imaging, studying chromatin inside live cells comes with challenges—it’s tiny, constantly moving, and influenced by countless molecular interactions. This is where computational modelling plays a critical role.

Scientists use molecular simulations to explore how chromatin behaves under different conditions. These models allow researchers to predict how chromatin proteins interact to form condensates, test how changes in charge, crowding, or chemical modifications affect phase separation and simulate long-term chromatin dynamics that would be impossible to observe in real-time.

By combining real-world microscopy with computational simulations, scientists are identifying the rules governing chromatin’s hidden phase transitions. Understanding these rules could one day allow us to control gene expression with unprecedented precision, a hopeful possibility for future medicine.

It could open doors to revolutionary therapies if scientists learn how to manipulate chromatin phase separation. From reversing diseases linked to faulty gene regulation to reprogramming cells for regenerative medicine, understanding chromatin’s hidden organisation may give us new ways to control life’s fundamental processes.

Maria Julia is a postdoctoral researcher in Computational Chemistry, and her current work focuses on computational models of protein and chromatin LLPS.