Mon. Dec 6th, 2021


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A cell stores all of its genetic material in its nucleus, in the form of chromosomes, but not all of it is stored there. The nucleus is also home to small bodies called nucleoli – clusters of proteins and RNA that help build ribosomes.

Using computer simulations, MIT chemists have now discovered how these bodies interact with chromosomes in the nucleus and how these interactions help the nucleols to exist as stable droplets in the nucleus.

Their results also suggest that chromatin-nuclear body interactions cause the genome to assume a gel-like structure, which helps promote stable interactions between the genome and the transcription machinery. These interactions help control gene expression.

“This model has inspired us to believe that the genome may have gel-like features that can help the system encode important contacts and help further translate those contacts into functional outputs,” said Bin Zhang, Pfizer-Laubach’s career development associate professor at chemistry at MIT, associate member of the Broad Institute of Harvard and MIT, and senior author of the study.

MIT graduate student Yifeng Qi is the lead author of the paper, which is shown today in Nature communication.

Modeling of drops

Much of Zhang’s research focuses on modeling the three – dimensional structure of the genome and analyzing how this structure affects gene regulation.

In the new study, he wanted to expand his modeling to include the nucleols. These small bodies, which are broken down at the beginning of cell division and then recovered later in the process, consist of more than a thousand different molecules of RNA and proteins. One of the key functions of the nucleols is to produce ribosomal RNA, a component of ribosomes.

Recent studies have suggested that nucleols exist as several fluid droplets. This was enigmatic because under normal conditions, several droplets would eventually have to fuse together into one large droplet to minimize the system’s surface tension, Zhang says.

“This is where the problem becomes interesting, because at its core, these multiple droplets can somehow remain stable over an entire cell cycle over about 24 hours,” he says.

To explore this phenomenon, Zhang and Qi used a technique called molecular dynamics simulation, which can model how a molecular system changes over time. At the beginning of the simulation, the proteins and RNA that make up the nucleols are randomly distributed throughout the nucleus, and the simulation tracks how they gradually form droplets.

In their simulation, the researchers also included chromatin, the substance that makes up chromosomes and contains proteins as well as DNA. Using data from previous experiments analyzing the structure of chromosomes, the MIT team calculated the interaction energy of individual chromosomes, enabling them to provide realistic representations of 3D genome structures.

Using this model, the researchers were able to observe how nucleolide droplets are formed. They found that if they modeled the nucleolar components on their own, without chromatin, they would eventually fuse into a large droplet, as expected. However, when chromatin was introduced into the model, the researchers found that the nucleols formed more droplets, just as they do in living cells.

The researchers also discovered why this happens: The nucleoli droplets become bound to specific areas of the chromatin, and once that happens, the chromatin acts as a trait that prevents the nucleols from fusing together.

“These forces essentially arrest the system in the droplets and prevent them from merging,” Zhang said. “Our study is the first to highlight the importance of this chromatin network, which could significantly slow down the fusion and stop the system in its droplet state.”

Gene control

The nucleoli are not the only small structures found in the nucleus – others include nuclear spots and nuclear lamina, a sheath that surrounds the genome and can bind to chromatin. Zhang’s group is now working on modeling the contributions of these nuclear structures, and their initial results suggest that they help give the genome more gel-like properties, Zhang says.

“This coupling that we have observed between chromatin and nuclear bodies is not specific to the nucleols. It is also general to other nuclear bodies,” he says. “This nuclear body concentration will fundamentally change the dynamics of the genome organization and will very likely transform the genome from a liquid into a gel.”

This gel-like state would make it easier for different regions of the chromatin to interact with each other than if the structure existed in a liquid state, he says. Maintaining stable interactions between distant regions of the genome is important because genes are often controlled by stretches of chromatin that are physically distant from them.

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More information:
Chromatin networks delay the coalescence of nuclei, Nature communication (2021). DOI: 10.1038 / s41467-021-27123-9

Provided by the Massachusetts Institute of Technology

Citation: How molecular clusters in the nucleus interact with chromosomes (2021, November 24) retrieved November 25, 2021 from

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