Ultimately, everything is governed by the laws of physics, including gene regulation. Why is it, then, that that the laws of physics are so sparingly consulted when biologists describe chromatin, that complex package of DNA and protein? Generally, it is assumed that chromatin is in the liquid state, and that regulatory proteins may drift about the nuclear depths, chancing upon their target DNA unless something near that DNA, something molecular or macromolecular, should present an obstacle. But perhaps things in the nucleus are a little less fluid, a little more organized at the supramolecular level, thanks to physical laws that pertain to states of matter.
This possibility seems a little firmer now that University of Alberta researchers are describing what they observed after examining the physical state of chromatin in vitro and in vivo. The researchers, led by department of oncology professor Michael Hendzel, PhD, and collaborator Jeffrey Hansen, PhD, a professor at Colorado State University, are reporting that chromatin is neither a solid nor a liquid, but something more like a gel.
The scientists published their findings in the journal Cell, in an article titled, “Condensed Chromatin Behaves like a Solid on the Mesoscale In Vitro and in Living Cells.” The article suggests that thinking of chromatin as a gel could lead to a more accurate understanding of how the genome is encoded and decoded.
“[While] there is evidence for a liquid compartment associated with heterochromatin, we find that the chromatin, itself, is not in a liquid state,” the article’s authors wrote. “We, therefore, conclude that chromatin is a solid-like scaffold that can support the assembly of liquid-like compartments enriched in specific effector proteins that percolate throughout the fiber matrix.”
The article’s authors also introduced various physical scenarios to give their ideas form. “We all know the difference between water and ice, and we all understand that if you want to tie two things together, for example, you can’t do it with a liquid. You need a rope, something that has mechanical strength,” said Hendzel, who is also a member of the Cancer Research Institute of Northern Alberta (CRINA). “That’s what we’re talking about here.”
“Another way to look at it is that bone, muscle, and connective tissue all have very different physical properties, and if those physical properties break down somehow, it’s almost always associated with disease,” said Alan Underhill, PhD, associate professor in the department of oncology at University of Alberta, CRINA member, and contributor to the study. “In the case of chromatin, it’s about scaling this principle down to the level of the cell nucleus, because it is all connected.”
“What we’re seeing here bridges the biochemistry of cellular contents and the underlying physics, allowing us to get at the organizational principles—not just for cells, but the entire body,” he added.
“Our results reveal that condensed chromatin exists in a solid-like state whose properties resist external forces and create an elastic gel and provides a scaffold that supports liquid-liquid phase separation of chromatin binding proteins,” the article’s authors noted.
All of our chromosomes are made from chromatin, which is half histone (or structural) proteins and half DNA, organized into long strings with bead-like structures (nucleosomes) on them. Inside the nucleus of a cell, the chromatin fiber interacts with itself to condense into a chromosome. The chromatin fiber also supports gene expression and replication of chromosomal DNA. Although there is some understanding of the structures that make up a nucleus, how those structures are organized and the full extent of how the structures interact with each other is not well known.
The team’s findings bridge research done over the past 50 years on chromatin gels produced in the laboratory to demonstrate its existence in living cells, which has major implications for interpreting their elastic and mechanical properties, Hendzel explained.
For example, recent studies have shown that the deformability of chromatin in cancer cells is an important determinant of their ability to squeeze through small spaces to travel outside a tumor and metastasize elsewhere in the body—something that may become easier to explain if it turns out that there are times when the chromatin gel may become less firm.
In cancer cells, chromatin may become less sticky if its histone part undergoes certain chemical changes. This process may be all the more relevant to cancer researchers if it occurs along with a shift in chromatin’s gel state, a process that would reduce the strength of the gel, making it more deformable and enabling cancer cells to spread through the body. Defining how the gel state is regulated could lead to new approaches to prevent metastasis by finding drugs that maintain the chromatin gel in a more rigid state.
A better understanding of chromatin could also affect cancer diagnosis, Underhill said.
“The texture and appearance of chromatin is something pathologists have used to do clinical assessment on tumor samples from patients,” he said. “It’s really looking at how the chromatin is organized within the nucleus that allows them to make insight into that clinical diagnosis. So, now that’s a process that we can reframe in a new context of the material state of the chromatin.”
Hendzel said he is confident the discovery of the gel-like state of chromatin will provide a guiding principle for future research seeking to understand how the material properties of chromatin shape the function of the nucleus to ensure the health of cells and the organisms they make up.
“One of the most significant things to me is that this research highlights how limited our knowledge is in this area,” he said. “Currently, we are focused on testing the widely held belief that the physical size of molecules determines their ability to access the DNA. Our ongoing experiments suggest that this too may be incorrect, and we are quite excited about learning new mechanisms that control access to DNA based on the properties of the chromatin gel and the liquid microenvironments that assemble around it.”
“I think it forces us to go back and look at what’s in textbooks and reinterpret a lot of that information in the context of whether ‘this is a liquid,’ or ‘this is a gel’ in terms of how the process actually takes place,” added Underhill. “That will have a lot of impact on how we actually think about things moving forward and how we design experiments and interpret them.”
