A new understanding of the physical properties of chromatin may indicate how a genome is encoded and encoded

University of Alberta researchers have found an answer to a fundamental question in genomic biology that has plagued scientists since DNA was discovered: Inside the nucleus of our cells, which is the complex package of DNA and proteins called hard chromatin or liquid?

In a study published in the journal Cell, the research team, led by Department of Oncology professor Michael Hendzel and colleague Jeffrey Hansen of Colorado State University, found that chromatin is neither solid nor liquid, but something more like a gel.

Previously, fields like biochemistry worked under the assumption that chromatin and other elements of the nucleus were working in a molten state, Hendzel said. This new understanding of the physical properties of chromatin challenges that notion, which may lead to a more accurate understanding of how the genome is encoded and coded.

“We all know the difference between water and ice, and we all understand that if you want to connect two things together, for example, you can’t do it with liquid. You need a rope, something at has mechanical strength, “said Hendzel, who is also a member of the Northern Alberta Cancer Research Institute (CRINA).

“That’s what we’re talking about here. Right now, our understanding of gene regulation is largely based on the acceptance of freely moving and DNA-detecting proteins that do not have access to it. regulation but by blocking that movement. So this research could lead to very different ways of understanding gene expression. “

“Another way to look at it is that bone, muscle and connective tissue have very different physical properties, and if those physical features break down in some way, it is always associated with disease, “said Alan Underhill, associate professor in the Department of Oncology, CRINA Member and contributed to the study. “In terms of chromatin, it’s about scaling this principle down to the nucleus level of the cells, because it’s all connected.”

“What we are seeing here drains the biochemistry of cell content and the underlying physics, allowing us access to organizational principles – not just for cells, but for the whole body,” he said.

All of our chromosomes are made up of chromatin, which is half histone (or structural) proteins and half DNA, organized in long rows with bead-like structures (nucleosomes) on them. Inside a cell nucleus, the chromatin fiber interacts by itself to awaken into a chromosome.

The chromatin fiber also supports gene expression and reproduction of chromosomal DNA. Although there is some understanding of the structures that make up a nucleus, it is not known with certainty how these structures are organized and the full extent of how the structures interact with each other.

The team’s findings examine a bridge made over the past 50 years on chromatin gels that were removed in the laboratory to show that it is in living cells, at its has a significant impact on defining their elastic and mechanical properties, Hendzel explained.

For example, recent studies have shown that chromatin deformability in cancer cells is an important test of their ability to push through small areas to travel outside a tumor and metastasize elsewhere in the body – something that it is much easier to explain whether chromatin is like a gel than a liquid.

Cancer cells do this by chemically altering the histone part of the chromatin to make it less sticky, Hendzel said.

Based on the new research, this can now be defined as a process that reduces the strength of the gel, makes it more deformable and allows cancer cells to spread through the body.

Explaining how this gel state is regulated could lead to new approaches to prevent metastasis by finding drugs that keep the gel chromatin in a harder state.

A better understanding of chromatin could influence cancer diagnosis, Underhill said.

“The texture and appearance of chromatin is something that pathologists have used to clinically evaluate tumor samples from patients,” he said. “It really looks at how the chromatin is organized within the nucleus that allows them to gain insight into that clinical diagnosis. So now that’s a process we can re-do. -update in the new context of the state of chromatin products. “

Hendzel said he is confident that the detection of a gel-like chromatin state will provide a guiding principle for future research that seeks to understand how the properties of chromatin products shape the function of the nucleus to ensure cell health. and the organisms they make up.

“One of the most important things for me is that this research highlights how limited our knowledge in this area is,” he said.

“Right now, our focus is on testing the widespread belief that molecular body size determines their ability to access DNA. Our ongoing tests suggest that this may be wrong. We are also excited to learn new ways to control DNA access based on the properties of the chromatin gel and the liquid microenvironments that accumulate around it. “

I think it makes us go back and look at the contents of textbooks and redefine 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 takes place. This will have a huge impact on how we think about moving things forward and how we design and interpret experiments. “

Alan Underhill, CRINA Member and Research Assistant, A.ssociate P.rofessor, Department of Oncology, Faculty of Science & Dentistry, University of Alberta