A microscope image of light blue dots that form the shape of cell nuclei. Pink dots and inside the nuclei represent bimolecular condensates.

Study Reveals How RNA Organizes Cellular Proteins

By Amy Pavlak Laird Email Amy Pavlak Laird

Heidi Opdyke

Molecules don鈥檛 just float around inside cells. Many gather into tiny, liquid-like droplets that form and dissolve as conditions change. These flexible structures, called biomolecular condensates, help organize chemical reactions, giving cells a dynamic, ever-shifting interior that鈥檚 like a lava lamp in motion.听

Even though these droplets are constantly shifting, scientists are finding that they actually organize into distinct patterns 鈥� and that those patterns are disrupted in diseases like cancer and neurodegeneration.听

A new study from 麻豆官网 identifies a mechanism that controls how these patterns form and how they play a key role in a cell鈥檚 function. The work appears in .听

鈥淭his research speaks to an entirely new field of studying how condensates are arranged in a cell,鈥� said Jonathan Henninger, assistant professor in the Department of Biological Sciences. 鈥淢any condensates show very different patterns throughout cells, but we鈥檙e not sure why or what function this serves. This study answers that question for one type of condensate.鈥澨�

Henninger and his team focused on the nucleolus, a large condensate inside the cell鈥檚 nucleus. Like the Russian matryoshka nested dolls, a smattering of smaller condensates exist inside the nucleolus. These smaller condensates manufacture millions of ribosomal RNA molecules, which are core components of ribosomes, the cell鈥檚 protein-making machinery.听

The team found that the condensates in the nucleolus arrange themselves in a distributed pattern, spreading out across the nucleolus instead of gathering in a more central location. Henninger and his colleagues set out to answer some key questions about this arrangement.

鈥淲hy do they all need to be separate from each other? Why can鈥檛 it just be one big blob? Well, it turns out that a distributed system is a lot more efficient than a centralized system,鈥� Henninger said.听

The left of the image shows a cell under the microscope, gray with green dots clustered inside. The right shows a diagram of condensates as small balls of varying spacing and number.
Condensates (the green dots) in the nucleolus arrange themselves in a distributed pattern, spreading out across the nucleolus instead of gathering in a more central location.

Each condensate acts like a small workstation, concentrating molecules to speed up production of ribosomal RNA. Spreading those workstations across the nucleolus helps the system run more smoothly. Henninger compares it to Amazon鈥檚 network of distributed warehouses, which deliver goods faster than a single centralized hub.听

鈥淓volution seems to strike a balance by grouping condensates enough to work efficiently, but not so much that the system becomes hard to control or slows down the next step,鈥� Henninger said.听

The researchers found that the ribosomal RNA itself helps to maintain this pattern. So, in effect, the product of the condensate (ribosomal RNA) is what controls how the condensates are organized, providing an active feedback loop.听

When that organization breaks down, so does function. The team showed that disrupting condensate patterns interferes with RNA processing, ultimately preventing the proper assembly of ribosomes.听

鈥淭his is important because many cancers require substantial protein synthesis, which is done by the ribosome. This could open up new ways of targeting cancer cells by altering the patterning of their condensates,鈥� Henninger said.听

To understand the underlying mechanism, the researchers combined physics-based modeling with live-cell imaging. Their simulations showed that when RNA production stops, condensates merge into fewer, larger droplets. When RNA production continues, the droplets maintain a stable size and spacing. Live-cell imaging confirmed these results.听

The findings suggest that RNA does more than carry instructions for protein assembly or act as a scaffold for protein complexes. It also helps control the size, spacing and organization of condensates inside the nucleolus.听

Haoran Wang stands next to a microscope. He is wearing a blue lab coat. Jon Henninger sits next to Haoran next to a computer monitor showing the microscope images.
Haoran Wang, a Ph.D. student in the Department of Biological Sciences, and Jonathan Henninger (right) in the lab.

The study also highlights the importance of the mesoscale 鈥� the level between individual molecules and the whole cell.

鈥淲e know a great deal about molecules and about whole cells, but this intermediate layer remains largely unexplored,鈥� Henninger said. 鈥淎nd this space is really important, especially in disease because it becomes disrupted. There鈥檚 a growing list of condensateopathies that are mesoscale defects associated with disease.鈥澨�

Beyond the nucleolus, the work provides a framework for studying how condensates are organized across many cellular systems in the nucleus, including the synthesis of messenger RNAs from genes. The results suggest that cells actively tune these patterns, using RNA production and molecular interactions to control how condensates form, space out and function.听

In addition to Henninger, the research team represents a joint effort among biologists and physicists, including: Carnegie Mellon Biological Sciences Ph.D. student Haoran Wang; Andriy Goychuk at Germany鈥檚 Helmholtz Centre for Infection Research; Salman Banani at The University of Chicago; Pradeep Natarajan, Mehran Kardar and Arup Chakraborty at the Massachusetts Institute of Technology; Ming M. Zheng at the Broad Institute of MIT and Harvard; Giuseppe Dall鈥橝gnese at the Whitehead Institute for Biomedical Research; and Richard A. Young at the Whitehead Institute for Biomedical Research and MIT. The work was supported by an early investigator grant from the Shurl and Kay Curci Foundation.