New comprehension of physical properties of chromatin may show how genome is encoded and decoded

Overview

• Post By : Kumar Jeetendra


• Source: University of Alberta Faculty of Medicine & Dentistry


• Date: 21 Dec,2020

University of Alberta researchers have found an answer to a basic question in genomic biology that has eluded scientists because the discovery of DNA: Over the nucleus of our cells, is the complex package of DNA and proteins called chromatin a solid or a liquid?

Previously, fields like biochemistry operated under the premise that chromatin and other elements of the nucleus operated in a liquid state, Hendzel said. This new understanding of the physical properties of chromatin challenges that idea, and may result in a more accurate understanding of how the genome is encoded and decoded.

“We all know the difference between ice and water, and most of us understand that in the event that you want to tie two things together, by way of example, you can not do it with a liquid. You require a rope, something which has mechanical power,” stated Hendzel, who is also a member of the Cancer Research Institute of Northern Alberta (CRINA).

“That’s what we’re talking about here. At the moment, all of our understanding of gene regulation is largely dependent on the assumption of freely moving proteins that locate DNA and whose availability is only governed by the blocking of that motion. So this research could potentially lead to quite different sorts of ways of understanding gene expression.”

“Another way to look at it’s that muscle, bone and connective tissue all have very different physical properties, and when those physical properties break down , it’s almost always associated with illness,” said Alan Underhill, associate professor in the Department of Oncology, CRINA member and contributor to the study. “In the event of chromatin, it’s about scaling this principle down to the level of the cell nucleus, because it is all connected.”

“What we are seeing here bridges the biochemistry of cellular contents and the underlying physics, allowing us to get in the organizational principles–not only for cells, but the whole body,” he added.

All our chromosomes are created 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 float to a chromosome.

The chromatin fiber also supports gene expression and replication of chromosomal DNA. Even though there is some understanding of the structures that make up a nucleus, how those structures are coordinated and the full extent of how the structures interact with each other isn’t well known.

The group’s findings bridge study done over the past 50 years on chromatin gels produced in the lab to demonstrate its existence in living cells, which has significant implications for interpreting their mechanical and elastic properties, Hendzel clarified.

By way of example, recent studies have shown that the deformability of chromatin in cancer cells is an important determinant of the ability to squeeze through small spaces to travel outside a tumour and metastasize elsewhere in the body–something that is much easier to explain if chromatin is gel-like rather than a liquid.

Cancer cells do that by changing the histone component of the chromatin to make it less sticky, Hendzel said.

Based on the new research, this is now explained as a process that reduces the strength of the gel, which makes it more deformable and enabling cancer cells to spread through the body.

Defining this gel state is regulated could lead to new approaches to prevent metastasis by discovering drugs that maintain the chromatin gel in a more rigid state.

A better comprehension of chromatin could also have an effect on cancer diagnosis, Underhill said.

“The texture and appearance of chromatin is something pathologists have used to do clinical evaluation on tumour samples from patients,” he said. “It is 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 procedure that we can reframe in a new context of the material state of the chromatin.”

Hendzel said he is confident the discovery of this gel-like state of chromatin will offer a guiding principle for future research trying to understand how the material properties of chromatin shape the function of the nucleus to ensure the health of cells and the organisms they constitute.

“One of the most crucial things to me is that this study highlights how limited our knowledge is in this region,” he said.

“Currently, we are focused on analyzing the widely held belief that the physical size of molecules determines their capacity to access the DNA. Our ongoing experiments suggest that this also may be incorrect, and we are very enthusiastic about learning new mechanisms that control access to DNA depending on the properties of the chromatin gel and the liquid microenvironments that build 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. That will have a lot of impact on how we actually think about things moving forward and how we design experiments and interpret them.”

Alan Underhill, CRINA Member and Study Contributor, Associate Professor, Department of Oncology, University of Alberta Faculty of Medicine & Dentistry